Cartilage homeostasis in health and rheumatic diseases

Mary B Goldring; Kenneth B Marcu

doi:10.1186/ar2592

Cartilage homeostasis in health and rheumatic diseases

Goldring, Mary B; Marcu, Kenneth B 2009-05-19 00:00:00 Available online http://arthritis-research.com/content/11/3/224 Review 1 2,3 Mary B Goldring and Kenneth B Marcu Research Division, Hospital for Special Surgery, affiliated with Weill College of Medicine of Cornell University, Caspary Research Building, 535 E. 70th Street, New York, NY 10021, USA Biochemistry and Cell Biology Department, Stony Brook University, Life Sciences Rm #330, Stony Brook, NY 11794, USA Centro Ricerca Biomedica Applicata, S. Orsola-Malpighi University Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy Corresponding author: Mary B Goldring, [email protected] Published: 19 May 2009 Arthritis Research & Therapy 2009, 11:224 (doi:10.1186/ar2592) This article is online at http://arthritis-research.com/content/11/3/224 © 2009 BioMed Central Ltd Abstract certain matrix proteins. During aging and joint disease, this equilibrium is disrupted and the rate of loss of collagens and As the cellular component of articular cartilage, chondrocytes are proteoglycans from the matrix may exceed the rate of responsible for maintaining in a low-turnover state the unique deposition of newly synthesized molecules. Originally con- composition and organization of the matrix that was determined during embryonic and postnatal development. In joint diseases, sidered an inert tissue, cartilage is now considered to cartilage homeostasis is disrupted by mechanisms that are driven respond to extrinsic factors that regulate gene expression by combinations of biological mediators that vary according to the and protein synthesis in chondrocytes. Numerous studies in disease process, including contributions from other joint tissues. In vitro and in vivo during the last two decades have confirmed osteoarthritis (OA), biomechanical stimuli predominate with up- that articular chondrocytes are able to respond to mechanical regulation of both catabolic and anabolic cytokines and recapitula- tion of developmental phenotypes, whereas in rheumatoid arthritis injury, joint instability due to genetic factors, and biological (RA), inflammation and catabolism drive cartilage loss. In vitro stimuli such as cytokines and growth and differentiation studies in chondrocytes have elucidated signaling pathways and factors that contribute to structural changes in the surround- transcription factors that orchestrate specific functions that promote ing cartilage matrix [1]. Mechanical influences on chondro- cartilage damage in both OA and RA. Thus, understanding how the cyte function are considered to be important in the patho- adult articular chondrocyte functions within its unique environment genesis of osteoarthritis (OA), but chondrocyte responses to will aid in the development of rational strategies to protect cartilage from damage resulting from joint disease. This review will cover molecular signals may vary in different regions, including the current knowledge about the specific cellular and biochemical calcified cartilage, and also occur at different stages over a mechanisms that regulate cartilage homeostasis and pathology. long time course (Figure 1). In rheumatoid arthritis (RA), the inflamed synovium is the major source of cytokines and Introduction proteinases that mediate cartilage destruction in areas Adult articular cartilage is an avascular tissue composed of a adjacent to the proliferating synovial pannus (Figure 2) [2]. specialized matrix of collagens, proteoglycans, and non- However, the basic cellular mechanisms regulating chondro- collagen proteins, in which chondrocytes constitute the cyte responses are very different in OA and RA. Moreover, unique cellular component. Although chondrocytes in this mechanistic insights from in vitro studies ideally should be context do not normally divide, they are assumed to maintain interpreted in light of direct analysis of human cartilage and the extracellular matrix (ECM) by low-turnover replacement of other joint tissues and studies in experimental models, inclu- ADAM = a disintegrin and metalloproteinase; ADAMTS = a disintegrin and metalloproteinase with thrombospondin-1 domains; AGE = advanced glycation end product; CD-RAP = cartilage-derived retinoic acid-sensitive protein; COL2A1 = collagen, type II, alpha 1; COMP = cartilage oligomeric matrix protein; COX-2 = cyclooxygenase 2; DDR-2 = discoidin domain receptor 2; DZC = deep zone chondrocyte; ECM = extracellular matrix; ERK = extracellular signal-regulated kinase; FRZB = frizzled-related protein 3; GADD45β = growth arrest and DNA damage 45 beta; GLUT = glucose transporter protein; HIF-1α = hypoxia-inducible factor-1-alpha; HMGB1 = high-mobility group protein 1; hTNFtg = human tumor necrosis factor transgenic; IGF-1 = insulin-like growth factor 1; Ihh = Indian hedgehog; IKK = IκB kinase; IL = interleukin; JNK = c-jun N-terminal kinase; MAPK = mitogen-activated protein kinase; MIA = melanoma inhibitory activity; MMP = matrix metalloproteinase; mPGES-1 = microsomal prostaglandin E synthase 1; MSC = mesenchymal stem cell; MZC = middle zone chondrocyte; NF-κB = nuclear factor-kappa-B; NO = nitric oxide; OA = osteoarthritis; PGE = prostaglandin E; PPAR = peroxisome proliferator-activated receptor; RA = rheumatoid arthritis; RAGE = receptor for advanced glycation end products; RANK = receptor activator of nuclear factor-kappa-B; RANKL = receptor activator of nuclear factor-kappa-B ligand; ROS = reactive oxygen species; SMAD = signal-transducing mothers against decapentaplegic; SOCS = suppressor of cytokine signaling; SZC = superficial zone chondrocyte; TGF-β = transforming growth factor-beta; TLR = Toll-like receptor; TNF-α = tumor necrosis factor-alpha; VEGF = vascular endothelial growth factor. Page 1 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu Figure 1 Cellular interactions in cartilage destruction in osteoarthritis. This scheme represents the destruction of the cartilage due to mechanical loading and biological factors. The induction of stress-induced intracellular signals, catabolic cytokines, including interleukin-1 (IL-1) and tumor necrosis factor- alpha (TNF-α), chemokines, and other inflammatory mediators produced by synovial cells and chondrocytes results in the upregulation of cartilage- degrading enzymes of the matrix metalloproteinase (MMP) and ADAMTS families. Matrix degradation products can feedback regulate these cellular events. Anabolic factors, including bone morphogenetic proteins (BMPs) and transforming growth factor-beta (TGF-β), may also be upregulated and participate in osteophyte formation. In addition to matrix loss, evidence of earlier changes, such as chondrocyte proliferation and hypertrophy, increased cartilage calcification with tidemark advancement, and microfractures with angiogenesis from the subchondral bone possibly mediated by vascular endothelial growth factor (VEGF) can be observed in late osteoarthritis samples obtained from patients after total joint replacement. ADAMTS, a disintegrin and metalloproteinase with thrombospondin-1 domains; C/EBP, CCAAT enhancer-binding protein; ESE1, epithelial-specific ETS; ETS, E26 transformation specific; GADD45β, growth arrest and DNA damage 45 beta; HIF-1α, hypoxia-inducible factor-1-alpha; NF-κB, nuclear factor-kappa-B; PA, plasminogen activator; TIMPs, tissue inhibitors of metalloproteinases. ding knockout and transgenic mice [3,4]. The examination of the collagen bundles are thickest and are arranged in a radial cartilage or chondrocytes from patients undergoing joint fashion, and (d) the calcified cartilage zone, located replacement has yielded less information in RA patients, in immediately below the tidemark and above the subchondral which cartilage damage is extensive, than studies of OA bone [5,6]. The calcified zone persists after growth plate patients. In both, the findings do not reflect early disease. closure as the ‘tidemark’ and serves as an important mecha- This review will cover current knowledge about the cellular nical buffer between the uncalcified articular cartilage and the and biochemical mechanisms of cartilage in health and subchondral bone. From the superficial to the deep zone, cell disease derived from studies over the past 10 years. density progressively decreases, whereas cell volume and the proportion of proteoglycan relative to collagen increase. Cartilage in health Cartilage matrix in healthy articular cartilage The interterritorial cartilage matrix, which is composed of a Articular cartilage is composed of four distinct regions: (a) fibrillar collagen network that bestows tensile strength, differs the superficial tangential (or gliding) zone, composed of thin from the territorial matrix closer to the cell, which contains collagen fibrils in tangential array and associated with a high type VI collagen microfibrils but little or no fibrillar collagen. concentration of decorin and a low concentration of aggre- The interterritorial collagen network consists primarily of type can, (b) the middle (or transitional) zone with radial bundles of II collagen fibrils with type XI collagen within the fibril and thicker collagen fibrils, (c) the deep (or radial) zone, in which type IX collagen integrated in the fibril surface with the non- Page 2 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 Figure 2 Cellular interactions in cartilage destruction in rheumatoid arthritis. This scheme represents the progressive destruction of the cartilage associated with the invading synovial pannus in rheumatoid arthritis. As a result of immune cell interactions involving T and B lymphocytes, monocytes/macrophages, and dendritic cells, a number of different cytokines are produced in the synovium due to the influx of inflammatory cells from the circulation and synovial cell hyperplasia. The induction of proinflammatory cytokines produced primarily in the synovium, but also by chondrocytes, results in the upregulation of cartilage-degrading enzymes at the cartilage-pannus junction. Chemokines, nitric oxide (NO), and prostaglandins (PGE ) also contribute to the inflammation and tissue catabolism. ADAMTS, a disintegrin and metalloproteinase with thrombospondin-1 domains; IFN-γ, interferon-gamma; IL, interleukin; MMP, matrix metalloproteinase; SDF-1, stromal derived factor 1; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; Treg, regulatory T (cell). collagen domain projecting outward, permitting association matrilins, and cartilage oligomeric matrix protein (COMP), are with other matrix components and retention of proteoglycans also present in the matrix. COMP acts as a catalyst in [7]. Collagen XXVII, a novel member of the fibrillar collagen collagen fibrillogenesis [9], and interactions between type IX family, also contributes to the formation of a stable cartilage collagen and COMP or matrilin-3 are essential for proper matrix [8]. formation and maintenance of the articular cartilage matrix [10,11]. Perlecan enhances fibril formation [12], and collagen Compressive resistance is bestowed by the large aggre- VI microfibrils connect to collagen II and aggrecan via gating proteoglycan aggrecan, which is attached to complexes of matrilin-1 and biglycan or decorin [13]. hyaluronic acid polymers via link protein. The half-life of aggrecan core protein ranges from 3 to 24 years, and the Chondrocyte physiology and function in healthy glycosaminoglycan components of aggrecan are synthesized articular cartilage more readily under low-turnover conditions, with more rapid Differences in the morphologies of zonal subpopulations of matrix turnover in the pericellular regions. The proteoglycans chondrocytes may reflect matrix composition and are are essential for protecting the collagen network, which has a ascribed largely to differences in the mechanical environment half-life of more than 100 years if not subjected to inappro- [14]. The superficial zone chondrocytes (SZCs) are small and priate degradation. A large number of other noncollagen flattened. The middle zone chondrocytes (MZCs) are rounded, molecules, including biglycan, decorin, fibromodulin, the and the deep zone chondrocytes (DZCs) are grouped in Page 3 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu columns or clusters. In vitro studies with isolated SZCs and connective tissues, a shift in equilibrium between anabolic and DZCs indicate that differences in the expression of mole- catabolic activities occurs in OA as a response to abnormal cules, such as lubricin (also known as superficial zone protein mechanical loading in conjunction with genetic abnormalities or or proteoglycan-4) and PTHrP by SZCs and Indian hedgehog injury to the cartilage and surrounding joint tissues. In RA, the (Ihh) and Runx2 by DZCs, may determine the zonal differ- inflamed synovium is the major source of cytokine-induced ences in matrix composition and function [15-17]. proteinases, although the episodic intra-articular inflammation with synovitis indicates that the synovium may also be a source How chondrocytes maintain their ECM under homeostatic of cytokines and cartilage-degrading proteinases in OA conditions has remained somewhat of a mystery since they [30,31]. However, in OA, these degradative enzymes are do not divide and the matrix isolates them from each other, produced primarily by chondrocytes due to inductive stimuli, but gene expression and protein synthesis may be activated including mechanical stress, injury with attendant by injury. Since the ECM normally shields chondrocytes, they destabilization, oxidative stress, cell-matrix interactions, and lack access to the vascular system and must rely on changes in growth factor responses and matrix during aging. facilitated glucose transport via constitutive glucose trans- porter proteins, GLUT3 and GLUT8 [18], and active Of the proteinases that degrade cartilage collagens and membrane transport systems [19]. Chondrocytes exist at low proteoglycans in joint disease, matrix metalloproteinases oxygen tension within the cartilage matrix, ranging from 10% (MMPs) and aggrecanases have been given the greatest at the surface to less than 1% in the deep zones. In vitro, attention because they degrade native collagens and proteo- chondrocytes adapt to low oxygen tensions by upregulating glycans [32-34]. These include the collagenases (MMP-1, hypoxia-inducible factor-1-alpha (HIF-1α), which can MMP-8, and MMP-13), the gelatinases (MMP-2 and MMP-9), stimulate expression of GLUTs [18], and angiogenic factors stromelysin-1 (MMP-3), and membrane type I (MT1) MMP such as vascular endothelial growth factor (VEGF) [20,21] as (MMP-14) [35]. MMP-10, similar to MMP-3, activates pro- well as a number of genes associated with cartilage anabo- collagenases, is detectable in OA and RA synovial fluids and lism and chondrocyte differentiation [22]. One of our joint tissues, and is produced in vitro by both the synovium laboratories has identified growth arrest and DNA damage 45 and chondrocytes in response to inflammatory cytokines [36]. beta (GADD45β), which previously was implicated as an anti- MMP-14, produced principally by RA synovial tissue, is impor- apoptotic factor during genotoxic stress and cell cycle arrest tant for synovial invasiveness [37], whereas the MMP-14 in other cell types as a survival factor in healthy articular produced by OA chondrocytes activates pro-MMP-13, which chondrocytes [23]. Thus, by modulating the intracellular in turn cleaves pro-MMP-9 [38]. Other MMPs, including expression of survival factors, including HIF-1α and MMP-16 and MMP-28 [32,39], and many members of the GADD45β, chondrocytes survive efficiently in the avascular reprolysin-related proteinases of the ADAM (a disintegrin and cartilage matrix and respond to environmental changes. metalloproteinase) family, including ADAM-17/TACE (tumor necrosis factor-alpha [TNF-α]-converting enzyme), are The aging process may affect the material properties of healthy expressed in cartilage, but their specific roles in cartilage cartilage by altering the content, composition, and structural damage in either OA or RA have yet to be defined [40-42]. organization of collagen and proteoglycan [24-26]. This has Although several of the MMPs, including MMP-3, MMP-8, been attributed to overall decreased anabolism and to the and MMP-14, are capable of degrading proteoglycans, accumulation of advanced glycation end products (AGEs) that ADAMTS (ADAM with thrombospondin-1 domains)-4 and enhance collagen cross-linking [27]. Unless perturbed, healthy ADAMTS-5 are now regarded as the principal aggrecan- chondrocytes remain in a postmitotic quiescent state degrading enzymes in cartilage [43,44]. Aggrecanase inhibi- throughout life, with their decreasing proliferative potential tors that target ADAMTS-5 have been developed and are being attributed to replicative senescence associated with awaiting opportunities for clinical trials in OA [45]. erosion of telomere length [28]. The accumulation of cartilage matrix proteins in the endoplasmic reticulum and Golgi of OA and RA differ with respect to the sites as well as the chondrocytes, which have been modified by oxidative stress origins of disrupted matrix homeostasis. In OA, proteoglycan during aging, may lead to decreased synthesis of cartilage loss and type II collagen cleavage initially occur at the matrix proteins and diminished cell survival [29]. cartilage surface, with evidence of pericellular damage in deeper zones as the lesion progresses [46]. In RA, intrinsic Cartilage in joint disease chondrocyte-derived chondrolytic activity is present at the The loss of balance between cartilage anabolism and cartilage-pannus junction, as well as in deeper zones of catabolism cartilage matrix [47], although elevated levels of MMPs in RA Although the etiologies of OA and RA are different, both synovial fluids likely originate from the synovium. There are diseases present states of inappropriate articular cartilage also differences in matrix synthetic responses in OA and RA. destruction, which is largely the result of elevated expression Whereas type II collagen synthesis is reduced in early RA and activities of proteolytic enzymes. Whereas these enzymes [48], there is evidence of compensatory increases in type II normally are involved in the formation, remodeling, and repair of collagen synthesis in deeper regions of OA cartilage [14]. Page 4 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 This is in agreement with findings of enhanced global syn- has received recent attention with respect to cartilage thesis and gene expression of aggrecan and type II collagen pathology. Human articular chondrocytes can express TLR1, in human OA compared with healthy cartilage [49-51]. TLR2, and TLR4, and the activation of TLR2 by IL-1, TNF-α, Importantly, microarray studies using full-thickness cartilage peptidoglycans, lipopolysaccharide, or fibronectin fragments have also shown that many collagen genes, including increases the production of MMPs, NO, prostaglandin E collagen, type II, alpha 1 (COL2A1), are upregulated in late- (PGE), and VEGF [68-73]. In immune complex-mediated stage OA [23,51]. The latter applies mainly to MZCs and arthritis, TLR4 regulates early-onset inflammation and DZCs, as revealed by laser capture microdissection, whereas cartilage destruction by IL-10-mediated upregulation of Fcγ this anabolic phenotype is less obvious in the degenerated receptor expression and enhanced cytokine production [74]. areas of the upper regions [52]. The IL-18 receptor shares homology with IL-1RI and has a TLR signaling domain. IL-18 has effects similar to IL-1 in Inflammation and cartilage destruction human chondrocytes and stimulates chondrocyte apoptosis, In vivo and in vitro studies have shown that chondrocytes although studies do not suggest a pivotal role in cartilage produce a number of inflammatory mediators, such as inter- destruction in RA [75,76]. IL-33, an ST2-TLR ligand, is leukin-1-beta (IL-1β) and TNF-α, which are present in RA or associated with endothelial cells in RA synovium, but its role OA joint tissues and fluids. Chondrocytes respond to these in cartilage destruction has not been examined [77]. Of proinflammatory cytokines by increasing the production of recent interest are the suppressor of cytokine signaling proteinases, prostaglandins, and nitric oxide (NO) [2,25]. The (SOCS) molecules, including SOCS3, which is induced by first recognition of IL-1 as a regulator of chondrocyte function IL-1 and acts as a negative feedback regulator during insulin- stems largely from work in in vitro culture models showing like growth factor 1 (IGF-1) desensitization in the absence of that activities derived from synovium or monocyte macro- NO by inhibiting insulin receptor substrate 1 (IRS-1) phages induce the production of cartilage-degrading protein- phosphorylation [78]. ases (reviewed in [2,53]). The increased production of prostaglandins by inflammatory IL-1, TNF-α, MMP-1, MMP-3, MMP-8, and MMP-13, and type cytokines is mediated via induction of the expression of not II collagen cleavage epitopes have been shown to colocalize only COX-2 but also microsomal PGE synthase 1 (mPGES-1) in matrix-depleted regions of RA cartilage [48,54] and OA [79,80]. In addition to opposing the induction of COX-2, cartilage [46,55]. In addition, chondrocytes express several inducible nitric oxide synthetase (iNOS), and MMPs and the chemokines as well as chemokine receptors that may suppression of aggrecan synthesis by IL-1, activators of the participate in cartilage catabolism [56,57]. IL-1β also induces peroxisome proliferator-activated receptor gamma (PPARγ), 12,14 other proinflammatory cytokines such as IL-17, which has including the endogenous ligand 15-deoxy-Δ prosta- similar effects on chondrocytes [58,59]. IL-32, a recently glandin J (PGJ ), inhibit IL-1-induced expression of mPGES- 2 2 discovered cytokine that induces TNF-α, IL-1β, IL-6, and 1 [81,82]. Recent evidence indicates that PPARα agonists chemokines, is also expressed in the synovia of RA patients may protect chondrocytes against IL-1-induced responses by and contributes to TNF-α-dependent inflammation and cartilage increasing the expression of IL-1Ra [83]. proteoglycan loss [60]. The importance of synergisms between IL-1 and TNF-α and with other cytokines, such as White adipose tissue has been proposed as a major source IL-17, IL-6, and oncostatin M, in RA or OA joints has been of both pro- and anti-inflammatory cytokines, including IL-1Ra inferred primarily from culture models [61-63]. The up- and IL-10 [84]. Roles for adipokines, identified originally as regulation of cyclooxygenase-2 (COX-2), MMP13, and NOS2 products of adipocytes, have received recent attention, not gene expression by IL-1β in chondrocytes and other cell only because of their relationship to obesity, but also because types is mediated by the induction and activation of a number they can have pro- or anti-inflammatory effects in joint tissues of transcription factors, including nuclear factor-kappa-B and may serve as a link between the neuroendocrine and (NF-κB), CCAAT enhancer-binding protein (C/EBP), activator immune systems [85]. Leptin expression is enhanced during protein 1 (AP-1), and E26 transformation specific family acute inflammation, correlating negatively with inflammatory members, which regulate stress- and inflammation-induced markers in RA sera [86]. The expression of leptin is elevated signaling [64]. IL-1β also uses these mechanisms to in OA cartilage and in osteophytes and it stimulates IGF-1 suppress the expression of a number of genes associated and transforming growth factor-beta-1 (TGF-β1) synthesis in with the differentiated chondrocyte phenotype, including chondrocytes [87]. Leptin synergizes with IL-1 or interferon- COL2A1 and cartilage-derived retinoic acid-sensitive protein/ gamma to increase NO production in chondrocytes [88], and melanoma inhibitory activity (CD-RAP/MIA) [64-66]. The role leptin deficiency attenuates inflammatory processes in experi- of epigenetics in regulating these cellular events in cartilage mental arthritis [89]. It has been proposed that the dys- is under current consideration [67]. regulated balance between leptin and other adipokines, such as adiponectin, promotes destructive inflammatory processes The IL-1R/Toll-like receptor (TLR) superfamily of receptors, [90]. Recent studies indicate that resistin plays a role in early which has a key role in innate immunity and inflammation, stages of trauma-induced OA and in RA at local sites of Page 5 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu inflammation and that serum resistin reflects inflammation and Stress responses in cartilage disease activity [91,92]. Injurious mechanical stress and cartilage matrix degradation products are capable of stimulating the same signaling Effects of mechanical loading pathways as those induced by inflammatory cytokines In young individuals without genetic abnormalities, bio- [98,106-109]. Along with extracellular signal-regulated kinase mechanical factors due to trauma are strongly implicated in 1/2 (ERK1/2), the key protein kinases in the c-jun N-terminal initiating the OA lesion. Mechanical disruption of cell-matrix kinase (JNK), p38 MAPK, and NF-κB signaling cascades are interactions may lead to aberrant chondrocyte behavior, activated, particularly in the upper zones of OA cartilage contributing to fibrillations, cell clusters, and changes in [110]. Furthermore, the engagement of integrin receptors by quantity, distribution, or composition of matrix proteins fibronectin or collagen fragments activates focal adhesion [93,94]. In the early stages of OA, transient increases in kinase signaling and transmits signals intersecting with ERK, chondrocyte proliferation and increased metabolic activity are JNK, and p38 pathways [111,112]. Cascades of multiple associated with a localized loss of proteoglycans at the protein kinases are involved in these responses, including cartilage surface followed by cleavage of type II collagen protein kinase Cζ, which is upregulated in OA cartilage and is (reviewed in [95,96]). These events result in increased water required for activation of NF-κB by IL-1 and TNF-α [113]. content and decreased tensile strength of the matrix as the However, it remains controversial whether inflammatory cyto- lesion progresses. kines are primary or secondary effectors of cartilage damage and defective repair mechanisms in OA since these same Chondrocytes can respond to direct biomechanical pertur- pathways also induce or amplify the expression of cytokine bation by upregulating synthetic activity or by increasing the genes. Interestingly, physiological loading may protect production of inflammatory cytokines, which are also against cartilage loss by inhibiting IκB kinase-beta (IKKβ) produced by other joint tissues. In vitro mechanical loading activity in the canonical NF-κB cascade and attenuating experiments have revealed that injurious static compression NF-κB transcriptional activity [114] as well as by inhibiting stimulates proteoglycan loss, damages the collagen network, TAK1 (TGF-β-activated kinase 1) phosphorylation [115]. In and reduces synthesis of cartilage matrix proteins, whereas addition, genetic factors that cause disruption of chondrocyte dynamic compression increases matrix synthetic activity [97]. differentiation and function and influence the composition and In response to traumatic injury, global gene expression is structure of the cartilage matrix may contribute to abnormal activated, resulting in increased expression of inflammatory biomechanics, independently of the influence of inflammation. mediators, cartilage-degrading proteinases, and stress response factors [98,99]. Neuronal signaling molecules, such Reactive oxygen species (ROS) play a critical role in as substance P and its receptor, NK1, and N-methyl-D- chondrocyte homeostasis, but during aging, trauma, and OA, aspartic acid receptors (NMDARs), which require glutamate partial oxygen variations and mechanical stress as well as and glycine binding for activation, have been implicated in inflammation induce abnormal ROS production, which mechanotransduction in chondrocytes in a recent study [100]. exceeds the antioxidant capacity leading to oxidative stress. ROS and attendant oxidative stress impair growth factor Chondrocytes have receptors for responding to mechanical responses, enhance senescence through telomere shorten- stimulation, many of which are also receptors for ECM ing, and impair mitochondrial function [28,116,117]. ROS components [101]. Among these are several of the integrins levels are also induced by activation of RAGE, the receptor that serve as receptors for fibronectin and type II collagen for AGEs, which regulates chondrocyte and synovial res- fragments, which upon activation stimulate the production of ponses in OA [118]. In chondrocytes, interaction of RAGE proteinases, cytokines, and chemokines [102]. Discoidin with S100A4, a member of the S100 family of calcium- domain receptor 2 (DDR-2), a receptor for native type II binding proteins, stimulates MMP-13 production via phos- collagen fibrils, is activated on chondrocytes via Ras/Raf/Mek phorylation of Pyk2, MAPKs, and NF-κB signaling [119]. signaling and preferentially induces MMP-13 via p38 RAGE expression and S100A1 release are stimulated in mitogen-activated protein kinase (MAPK); this is a universal chondrocytes in vitro and increased in OA cartilage. Trans- mechanism that occurs after loss of proteoglycans, not only glutaminase 1, which is induced by inflammation and stress, in genetic models, but also in surgical mouse OA and human transforms S100A1 into a procatabolic cytokine that signals OA [103]. On the other hand, in RA the cell-cell adhesion through RAGE and the p38 MAPK pathway to induce molecule, cadherin-11, is expressed at the interface between chondrocyte hypertrophy and aggrecan degradation [120]. In the RA synovial pannus and cartilage and facilitates cartilage experimental murine arthritis models, S100A8 and S100A9 invasion and erosion in mouse models in vivo and in human are involved in the upregulation and activation of MMPs and RA tissues in vitro and ex vivo [104] in a TNF-α-dependent aggrecanases [121,122]. In addition, high-mobility group manner [105]. Recent studies indicate that lubricin is an protein 1 (HMGB1), another important RAGE ligand and also important secreted product of chondrocytes, synovial cells, a chromatin architectural protein, is produced by inflamed and other joint tissues which is downregulated in OA and RA synovium and thus acts as a RAGE-dependent proinflam- and modulated by cytokines and growth factors [91,92]. matory cytokine in RA [123]. The differential regulation and Page 6 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 expression of GLUT isoforms by hypoxia, growth factors, and joints. Candidate gene studies and genome-wide linkage inflammatory cytokines may contribute to intracellular stress analyses have revealed polymorphisms or mutations in genes responses [124]. COX-2 is also involved in the chondrocyte encoding ECM and signaling molecules that may determine response to high shear stress, associated with reduced OA susceptibility [136-138]. Gender differences have been antioxidant capacity and increased apoptosis [125]. Modula- noted and gene defects may appear more prominently in tion of such intracellular stress response mechanisms may different joints [136,139]. Gene defects associated with provide strategies for novel therapies. congenital cartilage dysplasias that affect the formation of cartilage matrix and patterning of skeletal elements may Biomarkers of cartilage pathology adversely affect joint alignment and congruity and thus The recent development of assays for specific biological contribute to early onset of OA in these individuals [140]. markers, which reflect quantitative and dynamic changes in Although whole-genome linkage analyses of RA patients have the synthetic and degradation products of cartilage and bone not addressed cartilage specifically, this work has pointed to matrix components, has provided a means of identifying immunological pathways and inflammatory signals that may patients at risk for rapid joint damage and also for early modulate cartilage destruction [141]. monitoring of the efficacy of disease-modifying therapies. Molecules originating from the articular cartilage, including Genomic and proteomic analyses, which have been aggrecan fragments, which contain chondroitin sulfate and performed in cytokine-treated chondrocytes, in cartilage from keratan sulfate, type II collagen fragments, and collagen patients with OA, and in rheumatoid synovium, have provided pyridinoline cross-links, are usually released as degradation some insights into novel mechanisms that might govern products as a result of catabolic processes. Specific chondrocyte responses in both OA and RA [57,63,102,142]. antibodies that detect either synthetic or cleavage epitopes When coupled with biological analyses that address candi- have been developed to study biological markers of cartilage date genes, gene profiling studies of cartilage derived from metabolism in synovial fluids, sera, and urine of patients with OA patients with OA have also begun to yield new information or RA (reviewed in [126-129]). Aggrecan degradation about mediators and pathways [23,51,143,144]. Similarly, products are assayed using antibodies 846, 3B3(-), and 7D4 microarray analysis of cocultures of synovial fibroblasts with that detect chondroitin sulfate neoepitopes, 5D4 that detects chondrocytes in alginate has identified markers of inflam- keratan sulfate epitopes, and the VIDIPEN and NITEGE mation and cartilage destruction associated with RA antibodies that recognize aggrecanase and MMP cleavage pathogenesis [145]. sites, respectively, within the interglobular G1 domain of aggrecan [33]. Similarly, the C2C antibody (previously known Lessons from mouse models as Col2-3/4C ) has been used to detect specific Insight into cartilage pathology in RA has been gleaned from Long mono cleavage of the triple helix of type II collagen [48,129]. the examination of type II collagen-induced arthritis and other Increased ratios of C2C to the synthetic marker, CPII, are types of inflammatory arthritis in mice with transgenic over- associated with a greater likelihood of radiological expression or knockout of genes encoding cytokines, their progression in OA patients [130]. Other markers included receptors, or activators. These studies have led in part to the COMP [131]; YKL-40/HC-gp39, or chitinase 3-like protein 1 conclusion that TNF-α drives acute inflammation whereas (CH3L1), which is induced in chondrocytes by inflammatory IL-1 has a pivotal role in sustaining cartilage erosion [146]. In cytokines [132]; and CD-RAP, also known as MIA [133,134]. support of this concept, crossing arthritic human TNF trans- Such biomarker assays have been used as research tools genic (hTNFtg) mice with IL-1α- and β-deficient strains and are currently under evaluation for monitoring cartilage protected against cartilage erosion without affecting synovial degradation or repair in patient populations. C-reactive inflammation [147]. The success of anti-TNF-α therapy in protein, IL-6, and MMP-3 have also been identified as most but not all patients highlights the importance of potential biomarkers in both RA and OA patient populations. inflammation in joint destruction. A single marker has not proven to be sufficient, however, and the major challenge will be to apply such biomarkers to the In vivo studies have also shown that alterations in cartilage diagnosis and monitoring of disease in individual patients and matrix molecules or in regulators of chondrocyte differen- to correlate them with structural changes in cartilage tiation can lead to OA pathology. The importance of the fine identified by magnetic resonance imaging techniques [135]. protein network and ECM structural integrity in postnatal cartilage health is well documented in studies of deficiencies The genetics of cartilage pathology or mutations in cartilage matrix genes, including Col2a1, Results of epidemiological studies, analysis of patterns of Col9a1, Col11a1, aggrecan, matrilin-3, or fibromodulin alone familial clustering, twin studies, and the characterization of or together with biglycan, which lead to age-dependent rare genetic disorders suggest that genetic abnormalities can cartilage degeneration similar to that in OA patients result in early onset of OA and increased susceptibility to RA. [140,148,149]. Deficiency of Timp3 (tissue inhibitor of metallo- For example, twin studies have shown that the influence of proteinases 3) or postnatal overexpression of constitutively genetic factors may approach 70% in OA that affects certain active Mmp13 also promotes OA-like pathology [150,151]. Page 7 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu Importantly, surgically induced OA disease models in mutant of Mmp13 and Col10a1 in the mouse embryonic growth mice have also implicated ADAMTS5 [152,153], DDR-2 plate [165]. More recently, the findings of our groups suggest [103], and Runx2 [154] as contributors to the onset and/or that GADD45β contributes to the homeostasis of healthy and severity of OA joint disease. Knockout of IL-1β is also early OA articular chondrocytes as an effector of cell survival protective against OA induced by destabilization of the and as one of the factors induced by NF-κB that contributes medial meniscus [155]. Although single gene defects do not to the imbalance in matrix remodelling in OA cartilage by model all aspects of human OA, the loss or mutation of a suppressing COL2A1 gene expression [23] and that the NF- gene that is involved in the synthesis or remodeling of the κB activating kinases, IKKα and IKKβ, differentially contribute cartilage matrix may lead to the disruption of other gene to OA pathology by also regulating matrix remodelling in functions in chondrocytes, thus resulting in joint instability conjunction with chondrocyte differentiation [166]. and OA-like pathology. Thus, novel mechanistic insights into the initiation or progression of OA may be discovered by Endochondral ossification, in which the hypertrophic identifying intracellular effectors of ECM homeostasis and chondrocyte undergoes a stress response associated with remodelling in vitro and evaluating their functions in animal ECM remodelling, has been proposed as a ‘developmental models of OA disease. model’ to understand the contribution of exacerbated environ- mental stresses to OA pathology [167-170]. Changes in the Chondrogenesis, chondrocyte hypertrophy, calcified mineral content and thickness of the calcified cartilage and cartilage,, and bone in cartilage pathology the associated tidemark advancement may be related to During skeletal development, the chondrocytes arise from recapitulation of the hypertrophic phenotype, including mesenchymal progenitors to synthesize the templates, or COL10A1, MMP-13, and Runx2 gene expression, observed cartilage anlagen, for the developing limbs in a process in the deep zone of OA cartilage [167,171]. In addition to known as chondrogenesis [156]. Following mesenchymal COL10A1 and MMP-13, other chondrocyte terminal differen- condensation and chondroprogenitor cell differentiation, tiation-related genes, such as MMP-9 and Ihh, are detected chondrocytes undergo proliferation, terminal differentiation to in the vicinity of early OA lesions along with decreased levels hypertrophy, and apoptosis, whereby hypertrophic cartilage is of Sox9 mRNA [172]. However, Sox9 expression does not replaced by bone in endochondral ossification. A number of always localize with COL2A1 mRNA in adult articular signaling pathways and transcription factors play stage- cartilage [52,173]. Apoptosis is a rare event in OA cartilage specific roles in chondrogenesis and a similar sequence of but may be a consequence of the chondrocyte stress res- events occurs in the postnatal growth plate, leading to rapid ponse associated with hypertrophy [174]. Interestingly, one growth of the skeleton [64,156-158]. of our recent studies indicates that intracellular stress res- ponse genes are upregulated in early OA, whereas a number Chondrogenesis is orchestrated in part by Sox9 and Runx2, of genes encoding cartilage-specific and nonspecific two pivotal transcriptional regulators that determine the fate collagens and other matrix proteins are upregulated in late- of chondrocytes to remain within cartilage or undergo stage OA cartilage [23]. Moreover, articular chondrocytes in hypertrophic maturation prior to ossification and is also micromass culture show ‘phenotypic plasticity’ comparable to subject to complex regulation by interplay of the fibroblast mesenchymal stem cells (MSCs) undergoing chondro- growth factor, TGF-β, BMP, and Wnt signaling pathways genesis, by recapitulating processes akin to chondrocyte [159-162]. Differential signaling during chondrocyte matura- hypertrophy [175], which one of our labs recently has shown tion occurs via TGF-β-regulated signal-transducing mothers to be subject to differential control by canonical NF-κB against decapentaplegic (Smads) 2 and 3 that act to signaling and IKKα [166]. This process may also be maintain articular chondrocytes in an arrested state and modulated by Src kinases [176,177]. BMP-regulated Smads 1 and 5 that accelerate their differen- tiation. Sox9, which is essential for type II collagen (COL2A1) Additional supporting evidence for dysregulation of endo- gene expression, is most highly expressed in proliferating chondral ossification as a factor in OA pathology comes from chondrocytes and has opposing positive and negative effects genetic association studies identifying OA susceptibility on the early and late stages of chondrogenesis, respectively. genes across different populations [138,170,178]. These Sox9 cooperates with two related proteins, L-Sox5 and Sox6, include the genes encoding asporin (ASPN), a TGF-β- which are targets of Sox9 itself and function as architectural binding protein with biglycan and decorin sequence homology HMG-like chromatin modifiers. Moreover, BMP signaling, [179], secreted frizzled-related protein 3 (FRZB), a WNT/β- through the type I Bmpr1a and Bmpr1b receptors, redun- catenin signaling antagonist [180,181], and deiodinase 2 dantly drives chondrogenesis via Sox9, Sox5, and Sox6. In (DIO2), an enzyme that converts inactive thyroid hormone, addition, Runx2, which drives the terminal phase of chondro- T4, to active T3 [182]. The activation of WNT/β-catenin in genesis [163], is subject to direct inhibition by Sox9 [164]. In mature postnatal growth plate chondrocytes stimulates cooperation with BMP-induced Smads, Runx2 also upregu- hypertrophy, matrix mineralization, and expression of VEGF, lates GADD45β, a positive regulator of the terminal hyper- ADAMTS5, MMP-13, and several other MMPs [183]. trophic phase of chondrogenesis which drives the expression Findings from microarray analyses of bone from OA patients Page 8 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 [184] and in Frzb knockout mice [185] also suggest that fat, and muscle cells, are under investigation as sources of signaling modifications in the calcified cartilage could cartilage progenitor cells for cartilage tissue engineering contribute to increased subchondral plate thickness accom- [203-206]. Studies in vitro indicate that the same growth and panying tidemark advancement at the border with the differentiation factors that regulate different stages of articular cartilage and the angiogenesis observed at the cartilage development may be able to promote cartilage osteochondral junction [186]. Moreover, endochondral repair [207-209]. IGF-1 is a potent stimulator of proteoglycan ossification also contributes to the formation of osteophytes synthesis, particularly when combined with other anabolic [187-189]. Interestingly, HMGB1 released by hypertrophic factors, including BMPs [210,211]. Moreover, ex vivo gene cartilage, prior to the onset of programmed cell death, transfer of anabolic factors such as BMPs, TGF-β, and IGF-1 contributes to endochondral ossification by acting as a has been explored as an approach to promote differentiation chemotactic factor for osteoclasts at the growth plate [190], of autologous chondrocytes or MSCs before implantation and HMGB1-induced NF-κB signaling is also required for [212,213]. Recently, endochondral ossification has been cellular chemotaxis in response to HMGB1-RAGE engage- achieved with murine embryonic stem cells in tissue-engi- ment [191]. Thus, IKK-mediated NF-κB signaling not only neered constructs implanted in cranial bone of rats [214]. may intrinsically influence the differentiation of chondrocytes toward a hypertrophy-like state [166], but also could BMP-2 and BMP-7 (osteogenic protein 1) are currently subsequently drive aspects of intercellular communication approved for multiple indications in the area of bone fracture culminating in endochondral ossification [190]. repair and spinal fusion, but the capacity of BMPs and TGF-β to induce chondrocyte hypertrophy in cartilage repair models Changes in the periarticular and subchondral bone also and to promote osteophyte formation may prevent controlled occur in both RA and OA and may contribute to cartilage repair of articular cartilage in vivo [207]. Since the injection of pathology. Receptor activator of NFκB (RANK), a member of free TGF-β or adenovirus-mediated delivery of TGF-β pro- the TNF receptor family, RANK ligand (RANKL), and the motes fibrosis and osteophyte formation, while stimulating soluble receptor osteoprotegerin regulate osteoclast differen- proteoglycan synthesis in cartilage, the local application of tiation and activity and are important mediators of bone molecules that block endogenous TGF-β signaling, such as destruction in RA. IKKβ-mediated, but not IKKα-mediated, the soluble form of TGF-βRII, inhibitory SMADs, or the NF-κB signaling is associated with inflammation-induced physiological antagonist latency-associated peptide 1 (LAP-1), bone loss [192] and is also critical for the survival of osteo- has been proposed as a more effective strategy [188]. clast precursors by suppressing JNK-dependent apoptosis in Additional strategies include gene transfer of Sox9, alone or response to RANKL signaling [193]. IL-17 induces RANKL, together with L-Sox5 and Sox6, into MSCs ex vivo or into inducing bone destruction independently of IL-1 and bypass- joint tissues in vivo to more directly promote the expression ing the requirement for TNF in inflammatory arthritis [58]. of cartilage matrix genes [215,216]. Strategies to stably Although RANK and RANKL are expressed in adult articular express interfering RNAs in vivo could also provide a means chondrocytes, a direct action in cartilage has not been identi- of blocking dysregulated ECM remodelling or inappropriate fied [194]. Since cartilage destruction is not blocked directly endochondral ossification of articular chondrocytes. by the inhibition of RANKL, at least in inflammatory models, indirect effects may occur through protection of the bone Despite intensive investigation of cartilage repair strategies [195,196], as suggested by recent studies in experimental and the increased understanding of the cellular mechanisms models [197,198]. A link between RANKL and WNT has involved, many issues remain to be resolved. These include been suggested by findings in hTNFtg mice and RA tissues, the fabrication and maintenance of the repair tissue in the in which decreased β-catenin and high DKK-1, a WNT same zonal composition as the original cartilage, the recruit- inhibitor, were demonstrated in synovium and in cartilage ment and maintenance of cells with an appropriate chondro- adjacent to inflammatory tissue [199] (reviewed in [200]). In cyte phenotype, and integration of the repair construct with contrast, increased β-catenin was observed in OA cartilage the surrounding cartilage matrix [217]. These issues are also and conditional overexpression in mouse cartilage leads to compounded when cartilage loss is severe or when chronic premature chondrocyte differentiation and development of inflammation exists, as in RA. OA-like phenotype [201]. Interestingly, Runx2-dependent expression of RANKL occurs in hypertrophic chondrocytes at Conclusions the boundary next to the calcifying cartilage in the developing Laboratory investigations in vitro and in vivo regarding the growth plate [202]. role of the chondrocyte in remodeling the cartilage matrix in the RA and OA joint have identified novel molecules and Mesenchymal progenitor cells in cartilage and their use mechanisms and provided new understanding of the contri- in tissue engineering butions of known mediators. In RA, mediators involved in MSCs from bone marrow and other adult tissues, including immunomodulation and synovial cell function, including muscle, adipose tissue, and synovium or other tissue sites, cytokines, chemokines, and adhesion molecules, have primary which have the capacity to differentiate into cartilage, bone, roles in the inflammatory and catabolic processes in the joint, Page 9 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu 6. Goldring MB: Chapter 3: cartilage and chondrocytes. In Kelley’s Textbook of Rheumatology. 8th edition. Edited by Firestein GS, Budd RC, McInnes IB, Sergent JS, Harris ED, Ruddy S. Philadel- The Scientific Basis phia: WB Saunders, an imprint of Elsevier Inc.; 2008:37-69. 7. Eyre DR, Weis MA, Wu JJ: Articular cartilage collagen: an irre- of Rheumatology: placeable framework? Eur Cell Mater 2006, 12:57-63. A Decade of Progress 8. Plumb DA, Dhir V, Mironov A, Ferrara L, Poulsom R, Kadler KE, Thornton DJ, Briggs MD, Boot-Handford RP: Collagen XXVII is developmentally regulated and forms thin fibrillar structures This article is part of a special collection of reviews, The distinct from those of classical vertebrate fibrillar collagens. J Biol Chem 2007, 282:12791-12795. Scientific Basis of Rheumatology: A Decade of 9. Halasz K, Kassner A, Morgelin M, Heinegard D: COMP acts as a Progress, published to mark Arthritis Research & catalyst in collagen fibrillogenesis. J Biol Chem 2007, 282: 31166-31173. Therapy’s 10th anniversary. 10. Leighton MP, Nundlall S, Starborg T, Meadows RS, Suleman F, Knowles L, Wagener R, Thornton DJ, Kadler KE, Boot-Handford Other articles in this series can be found at: RP, Briggs MD: Decreased chondrocyte proliferation and dys- http://arthritis-research.com/sbr regulated apoptosis in the cartilage growth plate are key fea- tures of a murine model of epiphyseal dysplasia caused by a matn3 mutation. Hum Mol Genet 2007, 16:1728-1741. 11. Pirog-Garcia KA, Meadows RS, Knowles L, Heinegard D, Thorn- ton DJ, Kadler KE, Boot-Handford RP, Briggs MD: Reduced cell proliferation and increased apoptosis are significant patho- but they may also, directly or indirectly, promote cartilage logical mechanisms in a murine model of mild pseudoachon- damage. Despite our increasing knowledge of the mecha- droplasia resulting from a mutation in the C-terminal domain nisms regulating the responses of chondrocytes to anabolic of COMP. Hum Mol Genet 2007, 16:2072-2088. 12. Kvist AJ, Johnson AE, Mörgelin M, Gustafsson E, Bengtsson E, and catabolic factors involved in developing and adult Lindblom K, Aszódi A, Fässler R, Sasaki T, Timpl R, Aspberg A: cartilage, the development of disease-modifying therapies for Chondroitin sulfate perlecan enhances collagen fibril forma- OA patients has been elusive. In RA, in which significant tion. Implications for perlecan chondrodysplasias. J Biol Chem 2006, 281:33127-33139. advances have been achieved in our understanding of the 13. Wiberg C, Klatt AR, Wagener R, Paulsson M, Bateman JF, Heine- cellular interactions in the RA joint involving macrophages, T gard D, Morgelin M: Complexes of matrilin-1 and biglycan or decorin connect collagen VI microfibrils to both collagen II and B lymphocytes, and synovial fibroblasts, there is still a and aggrecan. J Biol Chem 2003, 278:37698-37704. need for therapeutic strategies that prevent the extensive 14. Poole AR, Guilak F, Abramson SB: Etiopathogenesis of cartilage and bone loss, despite the clinical success of anti- osteoarthritis. In Osteoarthritis: Diagnosis and Medical/Surgical Management. 4th edition. Edited by Moskowitz RW, Altman RW, TNF therapy for RA. Further work using the principles of cell Hochberg MC, Buckwalter JA, Goldberg VM. Philadelphia: Lippin- and molecular biology, such as those described in this cott, Williams, and Wilkins; 2007:27-49. 15. Cheng C, Conte E, Pleshko-Camacho N, Hidaka C: Differences review, will be necessary for uncovering new therapies for in matrix accumulation and hypertrophy in superficial and targeting cartilage destruction in both degenerative and deep zone chondrocytes are controlled by bone morpho- inflammatory joint disease. genetic protein. Matrix Biol 2007, 26:541-553. 16. Eleswarapu SV, Leipzig ND, Athanasiou KA: Gene expression of single articular chondrocytes. Cell Tissue Res 2007, 327:43- Competing interests The authors declare that they have no competing interests. 17. Chen X, Macica CM, Nasiri A, Broadus AE: Regulation of articu- lar chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Acknowledgments Arthritis Rheum 2008, 58:3788-3797. Research relating to this review was supported by National Institutes of 18. Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland Health (NIH) (Bethesda, MD, USA) grant AG022021 and by the Arthri- JA: Hypoxia inducible factor-1 and facilitative glucose trans- tis Foundation. KBM greatly acknowledges his collaborators in the Lab- porters GLUT1 and GLUT3: putative molecular components of oratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli (Bologna, the oxygen and glucose sensing apparatus in articular chon- Italy), in particular Rosa Maria Borzi, Eleonora Olivotto, Stefania Pagani, drocytes. Histol Histopathol 2005, 20:1327-1338. and Andrea Facchini. The research of KBM was supported in part by 19. Wilkins RJ, Browning JA, Ellory JC: Surviving in a matrix: mem- the Rizzoli Institute, the Carisbo Foundation of Bologna, a Rientro dei brane transport in articular chondrocytes. J Membr Biol 2000, Cervelli award, the MAIN EU FPVI Network of Excellence, and NIH 177:95-108. grant GM066882. 20. Lin C, McGough R, Aswad B, Block JA, Terek R: Hypoxia induces HIF-1a and VEGF expression in chondrosarcoma cells and chondrocytes. J Orthop Res 2004, 22:1175-1181. 21. Pufe T, Lemke A, Kurz B, Petersen W, Tillmann B, Grodzinsky AJ, References 1. Goldring MB, Goldring SR: Osteoarthritis. J Cell Physiol 2007, Mentlein R: Mechanical overload induces VEGF in cartilage discs via hypoxia-inducible factor. Am J Pathol 2004, 164:185- 213:626-634. 2. Dayer JM: The process of identifying and understanding 192. 22. Robins JC, Akeno N, Mukherjee A, Dalal RR, Aronow BJ, cytokines: from basic studies to treating rheumatic diseases. Best Pract Res Clin Rheumatol 2004, 18:31-45. Koopman P, Clemens TL: Hypoxia induces chondrocyte-spe- cific gene expression in mesenchymal cells in association 3. van de Loo FA, Geurts J, van den Berg WB: Gene therapy works in animal models of rheumatoid arthritis...so what! Curr with transcriptional activation of Sox9. Bone 2005, 37:313- Rheumatol Rep 2006, 8:386-393. 4. van den Berg WB: Lessons from animal models of osteoarthri- 23. Ijiri K, Zerbini LF, Peng H, Otu HH, Tsuchimochi K, Otero M, Dragomir C, Walsh N, Bierbaum BE, Mattingly D, van Flandern G, tis. Curr Rheumatol Rep 2008, 10:26-29. 5. Poole AR: Cartilage in health and disease. In Arthritis and Allied Komiya S, Aigner T, Libermann TA, Goldring MB: Differential expression of GADD45b in normal and osteoarthritic carti- Conditions: A Textbook of Rheumatology. 15th edition. Edited by Koopman WS. Philadelphia: Lippincott, Williams, and Wilkins; lage: Potential role in homeostasis of articular chondrocytes. Arthritis Rheum 2008, 58:2075-2087. 2005:223-269. Page 10 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 24. Dudhia J: Aggrecan, aging and assembly in articular cartilage. 45. Gilbert AM, Bursavich MG, Lombardi S, Georgiadis KE, Reifen- Cell Mol Life Sci 2005, 62:2241-2256. berg E, Flannery CR, Morris EA: N-((8-hydroxy-5-substituted- 25. Loeser RF: Molecular mechanisms of cartilage destruction: quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amin o-acetamide mechanics, inflammatory mediators, and aging collide. Arthri- inhibitors of ADAMTS-5 (Aggrecanase-2). Bioorg Med Chem tis Rheum 2006, 54:1357-1360. Lett 2008, 18:6454-6457. 26. Aigner T, Haag J, Martin J, Buckwalter J: Osteoarthritis: aging of 46. Wu W, Billinghurst RC, Pidoux I, Antoniou J, Zukor D, Tanzer M, matrix and cells—going for a remedy. Curr Drug Targets 2007, Poole AR: Sites of collagenase cleavage and denaturation of 8:325-331. type II collagen in aging and osteoarthritic articular cartilage 27. Verzijl N, Bank RA, TeKoppele JM, DeGroot J: AGEing and and their relationship to the distribution of matrix metallopro- osteoarthritis: a different perspective. Curr Opin Rheumatol teinase 1 and matrix metalloproteinase 13. Arthritis Rheum 2003, 15:616-622. 2002, 46:2087-2094. 28. Martin JA, Brown TD, Heiner AD, Buckwalter JA: Chondrocyte 47. Kane D, Jensen LE, Grehan S, Whitehead AS, Bresnihan B, senescence, joint loading and osteoarthritis. Clin Orthop Relat Fitzgerald O: Quantitation of metalloproteinase gene expres- Res 2004, (427 Suppl):S96-103. sion in rheumatoid and psoriatic arthritis synovial tissue distal 29. Yang L, Carlson SG, McBurney D, Horton WE Jr.: Multiple and proximal to the cartilage-pannus junction. J Rheumatol signals induce endoplasmic reticulum stress in both primary 2004, 31:1274-1280. and immortalized chondrocytes resulting in loss of differenti- 48. Fraser A, Fearon U, Billinghurst RC, Ionescu M, Reece R, Barwick ation, impaired cell growth, and apoptosis. J Biol Chem 2005, T, Emery P, Poole AR, Veale DJ: Turnover of type II collagen 280:31156-31165. and aggrecan in cartilage matrix at the onset of inflammatory 30. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan arthritis in humans: relationship to mediators of systemic and B: Synovial tissue inflammation in early and late osteoarthri- local inflammation. Arthritis Rheum 2003, 48:3085-3095. tis. Ann Rheum Dis 2005, 64:1263-1267. 49. Bau B, Gebhard PM, Haag J, Knorr T, Bartnik E, Aigner T: Rela- 31. Pearle AD, Scanzello CR, George S, Mandl LA, DiCarlo EF, Peter- tive messenger RNA expression profiling of collagenases and son M, Sculco TP, Crow MK: Elevated high-sensitivity C-reac- aggrecanases in human articular chondrocytes in vivo and in tive protein levels are associated with local inflammatory vitro. Arthritis Rheum 2002, 46:2648-2657. findings in patients with osteoarthritis. Osteoarthritis Cartilage 50. Hermansson M, Sawaji Y, Bolton M, Alexander S, Wallace A, 2007, 15:516-523. Begum S, Wait R, Saklatvala J: Proteomic analysis of articular 32. Cawston TE, Wilson AJ: Understanding the role of tissue cartilage shows increased type II collagen synthesis in degrading enzymes and their inhibitors in development and osteoarthritis and expression of inhibin bA (activin A), a regu- disease. Best Pract Res Clin Rheumatol 2006, 20:983-1002. latory molecule for chondrocytes. J Biol Chem 2004, 279: 33. Sandy JD: A contentious issue finds some clarity: on the inde- 43514-43521. pendent and complementary roles of aggrecanase activity 51. Aigner T, Fundel K, Saas J, Gebhard PM, Haag J, Weiss T, Zien A, and MMP activity in human joint aggrecanolysis. Osteoarthritis Obermayr F, Zimmer R, Bartnik E: Large-scale gene expression Cartilage 2006, 14:95-100. profiling reveals major pathogenetic pathways of cartilage 34. Rengel Y, Ospelt C, Gay S: Proteinases in the joint: clinical rel- degeneration in osteoarthritis. Arthritis Rheum 2006, 54:3533- evance of proteinases in joint destruction. Arthritis Res Ther 3544. 2007, 9:221. 52. Fukui N, Ikeda Y, Ohnuki T, Tanaka N, Hikita A, Mitomi H, Mori T, 35. Murphy G, Nagase H: Reappraising metalloproteinases in Juji T, Katsuragawa Y, Yamamoto S, Sawabe M, Yamane S, rheumatoid arthritis and osteoarthritis: destruction or repair? Suzuki R, Sandell LJ, Ochi T: Regional differences in chondro- Nat Clin Pract Rheumatol 2008, 4:128-135. cyte metabolism in osteoarthritis: a detailed analysis by laser 36. Barksby HE, Milner JM, Patterson AM, Peake NJ, Hui W, Robson capture microdissection. Arthritis Rheum 2008, 58:154-163. T, Lakey R, Middleton J, Cawston TE, Richards CD, Rowan AD: 53. Arend WP, Goldring MB: The development of anticytokine Matrix metalloproteinase 10 promotion of collagenolysis via therapeutics for rheumatic diseases. Arthritis Rheum 2008, 58: procollagenase activation: implications for cartilage degrada- S102-109. tion in arthritis. Arthritis Rheum 2006, 54:3244-3253. 54. Tetlow LC, Woolley DE: Comparative immunolocalization 37. Rutkauskaite E, Volkmer D, Shigeyama Y, Schedel J, Pap G, studies of collagenase 1 and collagenase 3 production in the Muller-Ladner U, Meinecke I, Alexander D, Gay RE, Drynda S, rheumatoid lesion, and by human chondrocytes and synovio- Neumann W, Michel BA, Aicher WK, Gay S, Pap T: Retroviral cytes in vitro. Br J Rheumatol 1998, 37:64-70. gene transfer of an antisense construct against membrane 55. Tetlow LC, Adlam DJ, Woolley DE: Matrix metalloproteinase type 1 matrix metalloproteinase reduces the invasiveness of and proinflammatory cytokine production by chondrocytes of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2005, human osteoarthritic cartilage. Arthritis Rheum 2001, 44:585- 52:2010-2014. 594. 38. Dreier R, Grassel S, Fuchs S, Schaumburger J, Bruckner P: Pro- 56. Borzi RM, Mazzetti I, Marcu KB, Facchini A: Chemokines in carti- MMP-9 is a specific macrophage product and is activated by lage degradation. Clin Orthop Relat Res 2004, (427 Suppl): osteoarthritic chondrocytes via MMP-3 or a MT1-MMP/MMP- S53-61. 13 cascade. Exp Cell Res 2004, 297:303-312. 57. Sandell LJ, Xing X, Franz C, Davies S, Chang LW, Patra D: Exu- 39. Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter berant expression of chemokine genes by adult human artic- S, Brockbank SM, Edwards DR, Parker AE, Clark IM: Expression ular chondrocytes in response to IL-1b. Osteoarthritis Cartilage profiling of metalloproteinases and their inhibitors in carti- 2008, 16:1560-1571. lage. Arthritis Rheum 2004, 50:131-141. 58. Lubberts E, Koenders MI, van den Berg WB: The role of T cell 40. Burrage PS, Huntington JT, Sporn MB, Brinckerhoff CE: Regula- interleukin-17 in conducting destructive arthritis: lessons tion of matrix metalloproteinase gene expression by a from animal models. Arthritis Res Ther 2005, 7:29-37. retinoid X receptor-specific ligand. Arthritis Rheum 2007, 56: 59. Koenders MI, Joosten LA, van den Berg WB: Potential new 892-904. targets in arthritis therapy: interleukin (IL)-17 and its relation 41. Murphy G, Lee MH: What are the roles of metalloproteinases to tumour necrosis factor and IL-1 in experimental arthritis. in cartilage and bone damage? Ann Rheum Dis 2005, 64 Ann Rheum Dis 2006, 65 Suppl 3:iii29-33. Suppl 4:iv44-47. 60. Joosten LA, Netea MG, Kim SH, Yoon DY, Oppers-Walgreen B, 42. Overall CM, Blobel CP: In search of partners: linking extracel- Radstake TR, Barrera P, van de Loo FA, Dinarello CA, van den lular proteases to substrates. Nat Rev Mol Cell Biol 2007, 8: Berg WB: IL-32, a proinflammatory cytokine in rheumatoid 245-257. arthritis. Proc Natl Acad Sci U S A 2006, 103:3298-3303. 43. Arner EC: Aggrecanase-mediated cartilage degradation. Curr 61. Rowan AD, Koshy PJ, Shingleton WD, Degnan BA, Heath JK, Ver- Opin Pharmacol 2002, 2:322-329. nallis AB, Spaull JR, Life PF, Hudson K, Cawston TE: Synergistic 44. Plaas A, Osborn B, Yoshihara Y, Bai Y, Bloom T, Nelson F, Mikecz effects of glycoprotein 130 binding cytokines in combination K, Sandy JD: Aggrecanolysis in human osteoarthritis: confocal with interleukin-1 on cartilage collagen breakdown. Arthritis localization and biochemical characterization of ADAMTS5- Rheum 2001, 44:1620-1632. hyaluronan complexes in articular cartilages. Osteoarthritis 62. Koshy PJ, Henderson N, Logan C, Life PF, Cawston TE, Rowan Cartilage 2007, 15:719-734. AD: Interleukin 17 induces cartilage collagen breakdown: Page 11 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu novel synergistic effects in combination with proinflammatory synthase 1 in osteoarthritic human cartilage: critical roles of cytokines. Ann Rheum Dis 2002, 61:704-713. the ERK-1/2 and p38 signaling pathways. Arthritis Rheum 63. Barksby HE, Hui W, Wappler I, Peters HH, Milner JM, Richards 2004, 50:2829-2838. CD, Cawston TE, Rowan AD: Interleukin-1 in combination with 80. Whiteman M, Spencer JP, Zhu YZ, Armstrong JS, Schantz JT: oncostatin M up-regulates multiple genes in chondrocytes: Peroxynitrite-modified collagen-II induces p38/ERK and NF- implications for cartilage destruction and repair. Arthritis kB-dependent synthesis of prostaglandin E2 and nitric oxide Rheum 2006, 54:540-550. in chondrogenically differentiated mesenchymal progenitor 64. Goldring MB, Sandell LJ: Transcriptional control of chondrocyte cells. Osteoarthritis Cartilage 2006, 14:460-470. gene expression. In OA, Inflammation and Degradation: A Con- 81. Cheng S, Afif H, Martel-Pelletier J, Pelletier JP, Li X, Farrajota K, tinuum. Edited by Buckwalter J, Lotz M, Stoltz JF. Amsterdam: Lavigne M, Fahmi H: Activation of peroxisome proliferator-acti- IOS Press; 2007:118-142. vated receptor g inhibits interleukin-1b-induced membrane- 65. Imamura T, Imamura C, Iwamoto Y, Sandell LJ: Transcriptional associated prostaglandin E2 synthase-1 expression in human Co-activators CREB-binding protein/p300 increase chondro- synovial fibroblasts by interfering with Egr-1. J Biol Chem cyte Cd-rap gene expression by multiple mechanisms includ- 2004, 279:22057-22065. ing sequestration of the repressor CCAAT/enhancer-binding 82. Li X, Afif H, Cheng S, Martel-Pelletier J, Pelletier JP, Ranger P, protein. J Biol Chem 2005, 280:16625-16634. Fahmi H: Expression and regulation of microsomal 66. Peng H, Tan L, Osaki M, Zhan Y, Ijiri K, Tsuchimochi K, Otero M, prostaglandin E synthase-1 in human osteoarthritic cartilage Wang H, Choy BK, Grall FT, Gu X, Libermann TA, Oettgen P, and chondrocytes. J Rheumatol 2005, 32:887-895. Goldring MB: ESE-1 is a potent repressor of type II collagen 83. Francois M, Richette P, Tsagris L, Fitting C, Lemay C, Benallaoua gene (COL2A1) transcription in human chondrocytes. J Cell M, Tahiri K, Corvol MT: Activation of the peroxisome prolifera- Physiol 2008, 215:562-573. tor-activated receptor a pathway potentiates interleukin-1 67. Roach HI, Yamada N, Cheung KS, Tilley S, Clarke NM, Oreffo receptor antagonist production in cytokine-treated chondro- RO, Kokubun S, Bronner F: Association between the abnormal cytes. Arthritis Rheum 2006, 54:1233-1245. expression of matrix-degrading enzymes by human 84. Dayer JM, Chicheportiche R, Juge-Aubry C, Meier C: Adipose osteoarthritic chondrocytes and demethylation of specific tissue has anti-inflammatory properties: focus on IL-1 recep- CpG sites in the promoter regions. Arthritis Rheum 2005, 52: tor antagonist (IL-1Ra). Ann N Y Acad Sci 2006, 1069:444- 3110-3124. 453. 68. Kim HA, Cho ML, Choi HY, Yoon CS, Jhun JY, Oh HJ, Kim HY: 85. Otero M, Lago R, Gomez R, Dieguez C, Lago F, Gomez-Reino J, The catabolic pathway mediated by Toll-like receptors in Gualillo O: Towards a pro-inflammatory and immunomodula- human osteoarthritic chondrocytes. Arthritis Rheum 2006, 54: tory emerging role of leptin. Rheumatology (Oxford) 2006, 45: 2152-2163. 944-950. 69. Su SL, Tsai CD, Lee CH, Salter DM, Lee HS: Expression and 86. Popa C, Netea MG, Radstake TR, van Riel PL, Barrera P, van der regulation of Toll-like receptor 2 by IL-1b and fibronectin frag- Meer JW: Markers of inflammation are negatively correlated ments in human articular chondrocytes. Osteoarthritis Carti- with serum leptin in rheumatoid arthritis. Ann Rheum Dis lage 2005, 13:879-886. 2005, 64:1195-1198. 70. Varoga D, Paulsen F, Mentlein R, Fay J, Kurz B, Schutz R, Wruck 87. Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, C, Goldring MB, Pufe T: TLR-2-mediated induction of vascular Pottie P: Evidence for a key role of leptin in osteoarthritis. endothelial growth factor (VEGF) in cartilage in septic joint Arthritis Rheum 2003, 48:3118-3129. disease. J Pathol 2006, 210:315-324. 88. Otero M, Lago R, Lago F, Reino JJ, Gualillo O: Signalling 71. Bobacz K, Sunk IG, Hofstaetter JG, Amoyo L, Toma CD, Akira S, pathway involved in nitric oxide synthase type II activation in Weichhart T, Saemann M, Smolen JS: Toll-like receptors and chondrocytes: synergistic effect of leptin with interleukin-1. chondrocytes: the lipopolysaccharide-induced decrease in Arthritis Res Ther 2005, 7:R581-591. cartilage matrix synthesis is dependent on the presence of 89. Palmer G, Aurrand-Lions M, Contassot E, Talabot-Ayer D, toll-like receptor 4 and antagonized by bone morphogenetic Ducrest-Gay D, Vesin C, Chobaz-Peclat V, Busso N, Gabay C: protein 7. Arthritis Rheum 2007, 56:1880-1893. Indirect effects of leptin receptor deficiency on lymphocyte 72. Haglund L, Bernier SM, Onnerfjord P, Recklies AD: Proteomic populations and immune response in db/db mice. J Immunol analysis of the LPS-induced stress response in rat chondro- 2006, 177:2899-2907. cytes reveals induction of innate immune response compo- 90. Lago F, Dieguez C, Gómez-Reino J, Gualillo O: The emerging nents in articular cartilage. Matrix Biol 2008, 27:107-118. role of adipokines as mediators of inflammation and immune 73. Zhang Q, Hui W, Litherland GJ, Barter MJ, Davidson R, Darrah C, responses. Cytokine Growth Factor Rev 2007, 18:313-325. Donell ST, Clark IM, Cawston TE, Robinson JH, Rowan AD, 91. Lee JH, Ort T, Ma K, Picha K, Carton J, Marsters PA, Lohmander Young DA: Differential Toll-like receptor-dependent collage- LS, Baribaud F, Song XY, Blake S: Resistin is elevated follow- nase expression in chondrocytes. Ann Rheum Dis 2008, 67: ing traumatic joint injury and causes matrix degradation and 1633-1641. release of inflammatory cytokines from articular cartilage in 74. van Lent PL, Blom AB, Grevers L, Sloetjes A, van den Berg WB: vitro. Osteoarthritis Cartilage 2008, Nov 1. [Epub ahead of print]. Toll-like receptor 4 induced FcgR expression potentiates early 92. Senolt L, Housa D, Vernerova Z, Jirasek T, Svobodova R, Veigl D, onset of joint inflammation and cartilage destruction during Anderlova K, Muller-Ladner U, Pavelka K, Haluzik M: Resistin in immune complex arthritis: Toll-like receptor 4 largely regu- rheumatoid arthritis synovial tissue, synovial fluid and serum. lates FcgR expression by interleukin 10. Ann Rheum Dis 2007, Ann Rheum Dis 2007, 66:458-463. 66:334-340. 93. Lee JH, Fitzgerald JB, Dimicco MA, Grodzinsky AJ: Mechanical 75. Dai SM, Shan ZZ, Nishioka K, Yudoh K: Implication of inter- injury of cartilage explants causes specific time-dependent leukin 18 in production of matrix metalloproteinases in articu- changes in chondrocyte gene expression. Arthritis Rheum lar chondrocytes in arthritis: direct effect on chondrocytes 2005, 52:2386-2395. may not be pivotal. Ann Rheum Dis 2005, 64:735-742. 94. Alexopoulos LG, Williams GM, Upton ML, Setton LA, Guilak F: 76. John T, Kohl B, Mobasheri A, Ertel W, Shakibaei M: Interleukin- Osteoarthritic changes in the biphasic mechanical properties 18 induces apoptosis in human articular chondrocytes. Histol of the chondrocyte pericellular matrix in articular cartilage. J Histopathol 2007, 22:469-482. Biomech 2005, 38:509-517. 77. Barksby HE, Lea SR, Preshaw PM, Taylor JJ: The expanding 95. Roach HI, Aigner T, Soder S, Haag J, Welkerling H: Pathobiology family of interleukin-1 cytokines and their role in destructive of osteoarthritis: pathomechanisms and potential therapeutic inflammatory disorders. Clin Exp Immunol 2007, 149:217-225. targets. Curr Drug Targets 2007, 8:271-282. 78. Smeets RL, Veenbergen S, Arntz OJ, Bennink MB, Joosten LA, 96. Sandell LJ: Anabolic factors in degenerative joint disease. Curr van den Berg WB, van de Loo FA: A novel role for suppressor Drug Targets 2007, 8:359-365. of cytokine signaling 3 in cartilage destruction via induction of 97. Guilak F, Fermor B, Keefe FJ, Kraus VB, Olson SA, Pisetsky DS, chondrocyte desensitization toward insulin-like growth factor. Setton LA, Weinberg JB: The role of biomechanics and inflam- Arthritis Rheum 2006, 54:1518-1528. mation in cartilage injury and repair. Clin Orthop Relat Res 79. Masuko-Hongo K, Berenbaum F, Humbert L, Salvat C, Goldring 2004, (423):17-26. MB, Thirion S: Up-regulation of microsomal prostaglandin E 98. Fitzgerald JB, Jin M, Dean D, Wood DJ, Zheng MH, Grodzinsky Page 12 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 AJ: Mechanical compression of cartilage explants induces by proteomics: a decrease in mitochondrial superoxide dis- multiple time-dependent gene expression patterns and mutase points to a redox imbalance. Mol Cell Proteomics involves intracellular calcium and cyclic AMP. J Biol Chem 2009, 8:172-189. 2004, 279:19502-19511. 118. Steenvoorden MM, Huizinga TW, Verzijl N, Bank RA, Ronday HK, 99. Kurz B, Lemke AK, Fay J, Pufe T, Grodzinsky AJ, Schunke M: Luning HA, Lafeber FP, Toes RE, DeGroot J: Activation of recep- Pathomechanisms of cartilage destruction by mechanical tor for advanced glycation end products in osteoarthritis injury. Ann Anat 2005, 187:473-485. leads to increased stimulation of chondrocytes and synovio- 100. Ramage L, Martel MA, Hardingham GE, Salter DM: NMDA recep- cytes. Arthritis Rheum 2006, 54:253-263. tor expression and activity in osteoarthritic human articular 119. Yammani RR, Carlson CS, Bresnick AR, Loeser RF: Increase in chondrocytes. Osteoarthritis Cartilage 2008, 16:1576-1584. production of matrix metalloproteinase 13 by human articular 101. Millward-Sadler SJ, Salter DM: Integrin-dependent signal cas- chondrocytes due to stimulation with S100A4: role of the cades in chondrocyte mechanotransduction. Ann Biomed Eng receptor for advanced glycation end products. Arthritis Rheum 2004, 32:435-446. 2006, 54:2901-2911. 102. Pulai JI, Chen H, Im HJ, Kumar S, Hanning C, Hegde PS, Loeser 120. Cecil DL, Terkeltaub R: Transamidation by transglutaminase 2 RF: NF-k B mediates the stimulation of cytokine and transforms S100A11 calgranulin into a procatabolic cytokine chemokine expression by human articular chondrocytes in for chondrocytes. J Immunol 2008, 180:8378-8385. response to fibronectin fragments. J Immunol 2005, 174:5781- 121. van Lent PL, Grevers L, Blom AB, Sloetjes A, Mort JS, Vogl T, 5788. Nacken W, van den Berg WB, Roth J: Myeloid-related proteins 103. Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K, Olsen BR, S100A8/S100A9 regulate joint inflammation and cartilage Goldring MB, Li Y: Increased expression of the collagen recep- destruction during antigen-induced arthritis. Ann Rheum Dis tor discoidin domain receptor 2 in articular cartilage as a key 2008, 67:1750-1758. event in the pathogenesis of osteoarthritis. Arthritis Rheum 122. van Lent PL, Grevers LC, Blom AB, Arntz OJ, van de Loo FA, van 2007, 56:2663-2673. der Kraan P, Abdollahi-Roodsaz S, Srikrishna G, Freeze H, Sloet- 104. Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GF, Chisaka O, jes A, Nacken W, Vogl T, Roth J, van den Berg WB: Stimulation Takeichi M, Brenner MB: Cadherin-11 in synovial lining forma- of chondrocyte-mediated cartilage destruction by S100A8 in tion and pathology in arthritis. Science 2007, 315:1006-1010. experimental murine arthritis. Arthritis Rheum 2008, 58:3776- 105. Vandooren B, Cantaert T, ter Borg M, Noordenbos T, Kuhlman R, 3787. Gerlag D, Bongartz T, Reedquist K, Tak PP, Baeten D: Tumor 123. Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, necrosis factor a drives cadherin 11 expression in rheumatoid Goto M, Inoue K, Yamada S, Ijiri K, Matsunaga S, Nakajima T, inflammation. Arthritis Rheum 2008, 58:3051-3062. Komiya S, Maruyama I: High mobility group box chromosomal 106. Fanning PJ, Emkey G, Smith RJ, Grodzinsky AJ, Szasz N, Trippel protein 1 plays a role in the pathogenesis of rheumatoid SB: Mechanical regulation of mitogen-activated protein arthritis as a novel cytokine. Arthritis Rheum 2003, 48:971-981. kinase signaling in articular cartilage. J Biol Chem 2003, 278: 124. Mobasheri A, Bondy CA, Moley K, Mendes AF, Rosa SC, Richard- 50940-50948. son SM, Hoyland JA, Barrett-Jolley R, Shakibaei M: Facilitative 107. Deschner J, Hofman CR, Piesco NP, Agarwal S: Signal trans- glucose transporters in articular chondrocytes. Expression, duction by mechanical strain in chondrocytes. Curr Opin Clin distribution and functional regulation of GLUT isoforms by Nutr Metab Care 2003, 6:289-293. hypoxia, hypoxia mimetics, growth factors and pro-inflamma- 108. Zhou Y, Millward-Sadler SJ, Lin H, Robinson H, Goldring M, Salter tory cytokines. Adv Anat Embryol Cell Biol 2008, 200:1 p fol- DM, Nuki G: Evidence for JNK-dependent up-regulation of lowing vi, 1-84. proteoglycan synthesis and for activation of JNK1 following 125. Healy ZR, Lee NH, Gao X, Goldring MB, Talalay P, Kensler TW, cyclical mechanical stimulation in a human chondrocyte Konstantopoulos K: Divergent responses of chondrocytes and culture model. Osteoarthritis Cartilage 2007, 15:884-893. endothelial cells to shear stress: cross-talk among COX-2, the 109. Knobloch TJ, Madhavan S, Nam J, Agarwal S Jr., Agarwal S: Reg- phase 2 response, and apoptosis. Proc Natl Acad Sci U S A ulation of chondrocytic gene expression by biomechanical 2005, 102:14010-14015. signals. Crit Rev Eukaryot Gene Expr 2008, 18:139-150. 126.Charni-Ben Tabassi N, Garnero P: Monitoring cartilage 110. Fan Z, Soder S, Oehler S, Fundel K, Aigner T: Activation of inter- turnover. Curr Rheumatol Rep 2007, 9:16-24. leukin-1 signaling cascades in normal and osteoarthritic artic- 127. Rousseau JC, Delmas PD: Biological markers in osteoarthritis. ular cartilage. Am J Pathol 2007, 171:938-946. Nat Clin Pract Rheumatol 2007, 3:346-356. 111.Ronziere MC, Aubert-Foucher E, Gouttenoire J, Bernaud J, 128. Dayer E, Dayer JM, Roux-Lombard P: Primer: the practical use of Herbage D, Mallein-Gerin F: Integrin a1b1 mediates collagen biological markers of rheumatic and systemic inflammatory induction of MMP-13 expression in MC615 chondrocytes. diseases. Nat Clin Pract Rheumatol 2007, 3:512-520. Biochim Biophys Acta 2005, 1746:55-64. 129. Henrotin Y, Addison S, Kraus V, Deberg M: Type II collagen 112. Loeser RF, Forsyth CB, Samarel AM, Im HJ: Fibronectin frag- markers in osteoarthritis: what do they indicate? Curr Opin ment activation of proline-rich tyrosine kinase PYK2 mediates Rheumatol 2007, 19:444-450. integrin signals regulating collagenase-3 expression by 130. Cahue S, Sharma L, Dunlop D, Ionescu M, Song J, Lobanok T, human chondrocytes through a protein kinase C-dependent King L, Poole AR: The ratio of type II collagen breakdown to pathway. J Biol Chem 2003, 278:24577-24585. synthesis and its relationship with the progression of knee 113. LaVallie ER, Chockalingam PS, Collins-Racie LA, Freeman BA, osteoarthritis. Osteoarthritis Cartilage 2007, 15:819-823. Keohan CC, Leitges M, Dorner AJ, Morris EA, Majumdar MK, Arai 131. Lindqvist E, Eberhardt K, Bendtzen K, Heinegard D, Saxne T: M: Protein kinase Cz is up-regulated in osteoarthritic cartilage Prognostic laboratory markers of joint damage in rheumatoid and is required for activation of NF-kB by tumor necrosis arthritis. Ann Rheum Dis 2005, 64:196-201. factor and interleukin-1 in articular chondrocytes. J Biol Chem 132. Baeten D, Steenbakkers PG, Rijnders AM, Boots AM, Veys EM, 2006, 281:24124-24137. De Keyser F: Detection of major histocompatibility complex/ 114. Dossumbekova A, Anghelina M, Madhavan S, He L, Quan N, human cartilage gp-39 complexes in rheumatoid arthritis syn- Knobloch T, Agarwal S: Biomechanical signals inhibit IKK ovitis as a specific and independent histologic marker. Arthri- activity to attenuate NF-kB transcription activity in inflamed tis Rheum 2004, 50:444-451. chondrocytes. Arthritis Rheum 2007, 56:3284-3296. 133. Saito S, Kondo S, Mishima S, Ishiguro N, Hasegawa Y, Sandell 115. Madhavan S, Anghelina M, Sjostrom D, Dossumbekova A, Gut- LJ, Iwata H: Analysis of cartilage-derived retinoic-acid-sensi- tridge DC, Agarwal S: Biomechanical signals suppress TAK1 tive protein (CD-RAP) in synovial fluid from patients with activation to inhibit NF-kB transcriptional activation in fibro- osteoarthritis and rheumatoid arthritis. J Bone Joint Surg Br chondrocytes. J Immunol 2007, 179:6246-6254. 2002, 84:1066-1069. 116. Grishko VI, Ho R, Wilson GL, Pearsall AW 4th: Diminished mito- 134. Vandooren B, Cantaert T, van Lierop MJ, Bos E, De Rycke L, Veys chondrial DNA integrity and repair capacity in OA chondro- EM, De Keyser F, Bresnihan B, Luyten FP, Verdonk PC, Tak PP, cytes. Osteoarthritis Cartilage 2009, 17:107-113. Boots AH, Baeten D: Melanoma inhibitory activity, a biomarker 117.Ruiz-Romero C, Calamia V, Mateos J, Carreira V, Martínez- related to chondrocyte anabolism, is reversibly suppressed by Gomariz M, Fernández M, Blanco FJ: Mitochondrial dysregula- proinflammatory cytokines in rheumatoid arthritis. Ann Rheum tion of osteoarthritic human articular chondrocytes analyzed Dis 2008, Jul 16. [Epub ahead of print]. Page 13 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu 135. Hunter DJ, Li J, LaValley M, Bauer DC, Nevitt M, DeGroot J, Poole Maruyama Z, Komori T, Sato S, Takeda S, Karsenty G, Nakamura R, Eyre D, Guermazi A, Gale D, Felson DT: Cartilage markers K, Chung UI, Kawaguchi H: Contribution of runt-related tran- and their association with cartilage loss on magnetic reso- scription factor 2 to the pathogenesis of osteoarthritis in mice nance imaging in knee osteoarthritis: the Boston Osteoarthri- after induction of knee joint instability. Arthritis Rheum 2006, tis Knee Study. Arthritis Res Ther 2007, 9:R108. 54:2462-2470. 136. Valdes AM, Loughlin J, Oene MV, Chapman K, Surdulescu GL, 155. Glasson SS, Blanchet TJ, Morris EA: The surgical destabiliza- Doherty M, Spector TD: Sex and ethnic differences in the asso- tion of the medial meniscus (DMM) model of osteoarthritis in ciation of ASPN, CALM1, COL2A1, COMP, and FRZB with the 129/SvEv mouse. Osteoarthritis Cartilage 2007, 15:1061- genetic susceptibility to osteoarthritis of the knee. Arthritis 1069. Rheum 2007, 56:137-146. 156. Goldring MB, Tsuchimochi K, Ijiri K: The control of chondrogen- 137. Valdes AM, Van Oene M, Hart DJ, Surdulescu GL, Loughlin J, esis. J Cell Biochem 2006, 97:33-44. Doherty M, Spector TD: Reproducible genetic associations 157. Lefebvre V, Smits P: Transcriptional control of chondrocyte fate between candidate genes and clinical knee osteoarthritis in and differentiation. Birth Defects Res C Embryo Today 2005, men and women. Arthritis Rheum 2006, 54:533-539. 75:200-212. 138. Loughlin J: Polymorphism in signal transduction is a major 158. Hidaka C, Goldring MB: Regulatory mechanisms of chondro- route through which osteoarthritis susceptibility is acting. genesis and implications for understanding articular cartilage Curr Opin Rheumatol 2005, 17:629-633. homeostasis. Curr Rheumatol Rev 2008, 4:136-147. 139. Bukulmez H, Matthews AL, Sullivan CM, Chen C, Kraay MJ, Elston 159. Haque T, Nakada S, Hamdy RC: A review of FGF18: its expres- RC, Moskowitz RW, Goldberg VM, Warman ML: Hip joint sion, signaling pathways and possible functions during replacement surgery for idiopathic osteoarthritis aggregates embryogenesis and post-natal development. Histol in families. Arthritis Res Ther 2006, 8:R25. Histopathol 2007, 22:97-105. 140. Li Y, Xu L, Olsen BR: Lessons from genetic forms of osteo- 160. Wu X, Shi W, Cao X: Multiplicity of BMP signaling in skeletal arthritis for the pathogenesis of the disease. Osteoarthritis development. Ann N Y Acad Sci 2007, 1116:29-49. Cartilage 2007, 15:1101-1105. 161.Yoon BS, Pogue R, Ovchinnikov DA, Yoshii I, Mishina Y, 141. Gregersen PK, Behrens TW: Genetics of autoimmune diseases— Behringer RR, Lyons KM: BMPs regulate multiple aspects of disorders of immune homeostasis. Nat Rev Genet 2006, 7: growth-plate chondrogenesis through opposing actions on 917-928. FGF pathways. Development 2006, 133:4667-4678. 142. Vincenti MP, Brinckerhoff CE: Early response genes induced in 162. Zhong N, Gersch RP, Hadjiargyrou M: Wnt signaling activation chondrocytes stimulated with the inflammatory cytokine inter- during bone regeneration and the role of Dishevelled in chon- leukin-1b. Arthritis Res 2001, 3:381-388. drocyte proliferation and differentiation. Bone 2006, 39:5-16. 143. Attur MG, Dave MN, Akamatsu M, Katoh M, Amin AR: A system 163. Dong YF, Soung do Y, Schwarz EM, O’Keefe RJ, Drissi H: Wnt biology approach to bioinformatics and functional genomics induction of chondrocyte hypertrophy through the Runx2 tran- in complex human diseases: arthritis. Curr Issues Mol Biol scription factor. J Cell Physiol 2006, 208:77-86. 2002, 4:129-146. 164. Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow 144. Sato T, Konomi K, Yamasaki S, Aratani S, Tsuchimochi K, Yok- D, Lee B: Dominance of SOX9 function over RUNX2 during ouchi M, Masuko-Hongo K, Yagishita N, Nakamura H, Komiya S, skeletogenesis. Proc Natl Acad Sci U S A 2006, 103:19004- Beppu M, Aoki H, Nishioka K, Nakajima T: Comparative analysis 19009. of gene expression profiles in intact and damaged regions of 165. Ijiri K, Zerbini LF, Peng H, Correa RG, Lu B, Walsh N, Zhao Y, human osteoarthritic cartilage. Arthritis Rheum 2006, 54:808- Taniguchi N, Huang XL, Otu H, Wang H, Wang JF, Komiya S, 817. Ducy P, Rahman MU, Flavell RA, Gravallese EM, Oettgen P, Liber- 145. Andreas K, Lubke C, Haupl T, Dehne T, Morawietz L, Ringe J, mann TA, Goldring MB: A novel role for GADD45b as a media- Kaps C, Sittinger M: Key regulatory molecules of cartilage tor of MMP-13 gene expression during chondrocyte terminal destruction in rheumatoid arthritis: an in vitro study. Arthritis differentiation. J Biol Chem 2005, 280:38544-38555. Res Ther 2008, 10:R9. 166. Olivotto E, Borzi RM, Vitellozzi R, Pagani S, Facchini A, Battistelli 146. van den Berg WB, van Riel PL: Uncoupling of inflammation and M, Penzo M, Li X, Flamigni F, Li J, Falcieri E, Facchini A, Marcu destruction in rheumatoid arthritis: myth or reality? Arthritis KB: Differential requirements for IKKa and IKKb in the differ- Rheum 2005, 52:995-999. entiation of primary human osteoarthritic chondrocytes. Arthri- 147. Zwerina J, Redlich K, Polzer K, Joosten L, Krönke G, Distler J, tis Rheum 2008, 58:227-239. Hess A, Pundt N, Pap T, Hoffmann O, Gasser J, Scheinecker C, 167. Aigner T, Bartnik E, Sohler F, Zimmer R: Functional genomics of Smolen JS, van den Berg W, Schett G: TNF-induced structural osteoarthritis: on the way to evaluate disease hypotheses. joint damage is mediated by IL-1. Proc Natl Acad Sci U S A Clin Orthop Relat Res 2004, (427 Suppl):S138-143. 2007, 104:11742-11747. 168. Drissi H, Zuscik M, Rosier R, O’Keefe R: Transcriptional regula- 148. Helminen HJ, Saamanen AM, Salminen H, Hyttinen MM: Trans- tion of chondrocyte maturation: potential involvement of tran- genic mouse models for studying the role of cartilage macro- scription factors in OA pathogenesis. Mol Aspects Med 2005, molecules in osteoarthritis. Rheumatology (Oxford) 2002, 41: 26:169-179. 848-856. 169. Terkeltaub RA: Aging, inflammation, and altered chondrocyte 149.Ameye LG, Young MF: Animal models of osteoarthritis: differentiation in articular cartilage calcification and lessons learned while seeking the ‘Holy Grail’. Curr Opin osteoarthritis. Amsterdam: IOS Press; 2007. Rheumatol 2006, 18:537-547. 170. Bos SD, Slagboom PE, Meulenbelt I: New insights into osteo- 150. Sahebjam S, Khokha R, Mort JS: Increased collagen and aggre- arthritis: early developmental features of an ageing-related can degradation with age in the joints of Timp3(-/-) mice. disease. Curr Opin Rheumatol 2008, 20:553-559. Arthritis Rheum 2007, 56:905-909. 171. Wang X, Manner PA, Horner A, Shum L, Tuan RS, Nuckolls GH: 151. Neuhold LA, Killar L, Zhao W, Sung ML, Warner L, Kulik J, Turner Regulation of MMP-13 expression by RUNX2 and FGF2 in J, Wu W, Billinghurst C, Meijers T, Poole AR, Babij P, DeGennaro osteoarthritic cartilage. Osteoarthritis Cartilage 2004, 12:963- LJ: Postnatal expression in hyaline cartilage of constitutively 973. active human collagenase-3 (MMP-13) induces osteoarthritis 172. Tchetina EV, Squires G, Poole AR: Increased type II collagen in mice. J Clin Invest 2001, 107:35-44. degradation and very early focal cartilage degeneration is 152. Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, associated with upregulation of chondrocyte differentiation Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris related genes in early human articular cartilage lesions. J EA: Deletion of active ADAMTS5 prevents cartilage degrada- Rheumatol 2005, 32:876-886. tion in a murine model of osteoarthritis. Nature 2005, 434:644- 173. Aigner T, Gebhard PM, Schmid E, Bau B, Harley V, Poschl E: 648. SOX9 expression does not correlate with type II collagen 153. Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker expression in adult articular chondrocytes. Matrix Biol 2003, CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang 22:363-372. AJ: ADAMTS5 is the major aggrecanase in mouse cartilage in 174. Aigner T, Kim HA, Roach HI: Apoptosis in osteoarthritis. Rheum vivo and in vitro. Nature 2005, 434:648-652. Dis Clin North Am 2004, 30:639-653, xi. 154. Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, 175. Tallheden T, Dennis JE, Lennon DP, Sjogren-Jansson E, Caplan Page 14 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 AI, Lindahl A: Phenotypic plasticity of human articular chondro- 194. Komuro H, Olee T, Kuhn K, Quach J, Brinson DC, Shikhman A, cytes. J Bone Joint Surg Am 2003, 85-A Suppl 2:93-100. Valbracht J, Creighton-Achermann L, Lotz M: The osteoprote- 176. Bursell L, Woods A, James CG, Pala D, Leask A, Beier F: Src gerin/receptor activator of nuclear factor kB/receptor activa- kinase inhibition promotes the chondrocyte phenotype. Arthri- tor of nuclear factor kB ligand system in cartilage. Arthritis tis Res Ther 2007, 9:R105. Rheum 2001, 44:2768-2776. 177. Pala D, Kapoor M, Woods A, Kennedy L, Liu S, Chen S, Bursell L, 195. Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y, Lyons KM, Carter DE, Beier F, Leask A: Focal adhesion kinase/ Benoist C, Gravallese EM: TRANCE/RANKL knockout mice are Src suppresses early chondrogenesis: central role of CCN2. J protected from bone erosion in a serum transfer model of Biol Chem 2008, 283:9239-9247. arthritis. Am J Pathol 2001, 159:1689-1699. 178.Valdes AM, Spector TD: The contribution of genes to 196. Schett G, Hayer S, Zwerina J, Redlich K, Smolen JS: Mecha- osteoarthritis. Rheum Dis Clin North Am 2008, 34:581-603. nisms of Disease: the link between RANKL and arthritic bone 179. Kizawa H, Kou I, Iida A, Sudo A, Miyamoto Y, Fukuda A, Mabuchi disease. Nat Clin Pract Rheumatol 2005, 1:47-54. A, Kotani A, Kawakami A, Yamamoto S, Uchida A, Nakamura K, 197. Kadri A, Ea HK, Bazille C, Hannouche D, Liote F, Cohen-Solal ME: Notoya K, Nakamura Y, Ikegawa S: An aspartic acid repeat poly- Osteoprotegerin inhibits cartilage degradation through an morphism in asporin inhibits chondrogenesis and increases effect on trabecular bone in murine experimental osteoarthri- susceptibility to osteoarthritis. Nat Genet 2005, 37:138-144. tis. Arthritis Rheum 2008, 58:2379-2386. 180. Lane NE, Lian K, Nevitt MC, Zmuda JM, Lui L, Li J, Wang J, 198. Kwan Tat S, Pelletier JP, Lajeunesse D, Fahmi H, Lavigne M, Fontecha M, Umblas N, Rosenbach M, de Leon P, Corr M: Friz- Martel-Pelletier J: The differential expression of osteoprote- zled-related protein variants are risk factors for hip gerin (OPG) and receptor activator of nuclear factor kB ligand osteoarthritis. Arthritis Rheum 2006, 54:1246-1254. (RANKL) in human osteoarthritic subchondral bone 181. Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, osteoblasts is an indicator of the metabolic state of these Southam L, Ferreira A, Ciesielski C, Carson DA, Corr M: Func- disease cells. Clin Exp Rheumatol 2008, 26:295-304. tional variants within the secreted frizzled-related protein 3 199. Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, gene are associated with hip osteoarthritis in females. Proc Korb A, Smolen J, Hoffmann M, Scheinecker C, van der Heide D, Natl Acad Sci U S A 2004, 101:9757-9762. Landewe R, Lacey D, Richards WG, Schett G: Dickkopf-1 is a 182. Meulenbelt I, Min JL, Bos S, Riyazi N, Houwing-Duistermaat JJ, master regulator of joint remodeling. Nat Med 2007, 13:156- van der Wijk HJ, Kroon HM, Nakajima M, Ikegawa S, Uitterlinden 163. AG, van Meurs JB, van der Deure WM, Visser TJ, Seymour AB, 200. Goldring SR, Goldring MB: Eating bone or adding it: the Wnt Lakenberg N, van der Breggen R, Kremer D, van Duijn CM, Klop- pathway decides. Nat Med 2007, 13:133-134. penburg M, Loughlin J, Slagboom PE: Identification of DIO2 as a 201. Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, Rosier R, O’Keefe new susceptibility locus for symptomatic osteoarthritis. Hum R, Zuscik M, Chen D: Activation of beta-catenin signaling in Mol Genet 2008, 17:1867-1875. articular chondrocytes leads to osteoarthritis-like phenotype 183. Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, in adult beta-catenin conditional activation mice. J Bone Miner Yamada Y, Costantini F, Wakisaka S, Pacifici M, Iwamoto M, Res 2009, 24:12-21. Enomoto-Iwamoto M: Developmental regulation of Wnt/b- 202. Kishimoto K, Kitazawa R, Kurosaka M, Maeda S, Kitazawa S: catenin signals is required for growth plate assembly, carti- Expression profile of genes related to osteoclastogenesis in lage integrity, and endochondral ossification. J Biol Chem mouse growth plate and articular cartilage. Histochem Cell 2005, 280:19185-19195. Biol 2006, 125:593-602. 184. Hopwood B, Tsykin A, Findlay DM, Fazzalari NL: Microarray gene 203. Barry FP, Murphy JM: Mesenchymal stem cells: clinical applica- expression profiling of osteoarthritic bone suggests altered tions and biological characterization. Int J Biochem Cell Biol bone remodelling, WNT and transforming growth factor-b/ 2004, 36:568-584. bone morphogenic protein signalling. Arthritis Res Ther 2007, 204.Caplan AI: Review: mesenchymal stem cells: cell-based 9:R100. reconstructive therapy in orthopedics. Tissue Eng 2005, 11: 185. Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten 1198-1211. J, Thomas JT, Luyten FP: Articular cartilage and biomechanical 205. Huang JI, Kazmi N, Durbhakula MM, Hering TM, Yoo JU, John- properties of the long bones in Frzb-knockout mice. Arthritis stone B: Chondrogenic potential of progenitor cells derived Rheum 2007, 56:4095-4103. from human bone marrow and adipose tissue: A patient- 186. Walsh DA, Bonnet CS, Turner EL, Wilson D, Situ M, McWilliams matched comparison. J Orthop Res 2005, 23:1383-1389. DF: Angiogenesis in the synovium and at the osteochondral 206. Palmer GD, Steinert A, Pascher A, Gouze E, Gouze JN, Betz O, junction in osteoarthritis. Osteoarthritis Cartilage 2007, 15:743- Johnstone B, Evans CH, Ghivizzani SC: Gene-induced chondro- 751. genesis of primary mesenchymal stem cells in vitro. Mol Ther 187. Burr DB: Anatomy and physiology of the mineralized tissues: 2005, 12:219-228. role in the pathogenesis of osteoarthrosis. Osteoarthritis Carti- 207.Goldring MB: Are bone morphogenetic proteins effective lage 2004, 12 Suppl A:S20-30. inducers of cartilage repair? Ex vivo transduction of muscle- 188. Blaney Davidson EN, van der Kraan PM, van den Berg WB: TGF- derived stem cells. Arthritis Rheum 2006, 54:387-389. b and osteoarthritis. Osteoarthritis Cartilage 2007, 15:597-604. 208. Kuroda R, Usas A, Kubo S, Corsi K, Peng H, Rose T, Cummins J, 189. van der Kraan PM, van den Berg WB: Osteophytes: relevance Fu FH, Huard J: Cartilage repair using bone morphogenetic and biology. Osteoarthritis Cartilage 2007, 15:237-244. protein 4 and muscle-derived stem cells. Arthritis Rheum 190. Taniguchi N, Yoshida K, Ito T, Tsuda M, Mishima Y, Furumatsu T, 2006, 54:433-442. Ronfani L, Abeyama K, Kawahara K, Komiya S, Maruyama I, Lotz 209. Magne D, Vinatier C, Julien M, Weiss P, Guicheux J: Mesenchy- M, Bianchi ME, Asahara H: Stage-specific secretion of HMGB1 mal stem cell therapy to rebuild cartilage. Trends Mol Med in cartilage regulates endochondral ossification. Mol Cell Biol 2005, 11:519-526. 2007, 27:5650-5663. 210. Loeser RF, Chubinskaya S, Pacione C, Im HJ: Basic fibroblast 191. Palumbo R, Galvez BG, Pusterla T, De Marchis F, Cossu G, growth factor inhibits the anabolic activity of insulin-like Marcu KB, Bianchi ME: Cells migrating to sites of tissue growth factor 1 and osteogenic protein 1 in adult human artic- damage in response to the danger signal HMGB1 require NF- ular chondrocytes. Arthritis Rheum 2005, 52:3910-3917. kB activation. J Cell Biol 2007, 179:33-40. 211.Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ: 192. Ruocco MG, Maeda S, Park JM, Lawrence T, Hsu LC, Cao Y, Genetic modification of chondrocytes with insulin-like growth Schett G, Wagner EF, Karin M: I{k}B kinase (IKK){b}, but not factor-1 enhances cartilage healing in an equine model. J IKK{a}, is a critical mediator of osteoclast survival and is Bone Joint Surg Br 2007, 89:672-685. required for inflammation-induced bone loss. J Exp Med 2005, 212. Evans CH: Novel biological approaches to the intra-articular 201:1677-1687. treatment of osteoarthritis. BioDrugs 2005, 19:355-362. 193. Otero JE, Dai S, Foglia D, Alhawagri M, Vacher J, Pasparakis M, 213. Lories RJ, Luyten FP: Bone morphogenetic protein signaling in Abu-Amer Y: Defective osteoclastogenesis by IKKb-null pre- joint homeostasis and disease. Cytokine Growth Factor Rev cursors is a result of receptor activator of NF-kB ligand 2005, 16:287-298. (RANKL)-induced JNK-dependent apoptosis and impaired dif- 214. Jukes JM, Both SK, Leusink A, Sterk LMT, van Blitterswijk CA, de ferentiation. J Biol Chem 2008, 283:24546-24553. Boer J: Endochondral bone tissue engineering using embry- Page 15 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu onic stem cells. Proc Natl Acad Sci USA 2008, 105:6840-6845. 215. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S, Takato T, Naka- mura K, Kawaguchi H, Ikegawa S, Chung UI: The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals suffi- cient for induction of permanent cartilage. Arthritis Rheum 2004, 50:3561-3573. 216. Tew SR, Li Y, Pothacharoen P, Tweats LM, Hawkins RE, Harding- ham TE: Retroviral transduction with SOX9 enhances re- expression of the chondrocyte phenotype in passaged osteoarthritic human articular chondrocytes. Osteoarthritis Cartilage 2005, 13:80-89. 217. Kuo CK, Li WJ, Mauck RL, Tuan RS: Cartilage tissue engineer- ing: its potential and uses. Curr Opin Rheumatol 2006, 18:64- Page 16 of 16 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arthritis Research & Therapy Pubmed Central http://www.deepdyve.com/lp/pubmed-central/cartilage-homeostasis-in-health-and-rheumatic-diseases-FIpUlnYXoo

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References (233)

C. Ruiz-Romero, V. Calamia, J. Mateos, V. Carreira, M. Martínez‐Gomariz, M. Fernández, F. Blanco (2009)
Mitochondrial Dysregulation of Osteoarthritic Human Articular Chondrocytes Analyzed by Proteomics
Molecular & Cellular Proteomics : MCP, 8
E. Rutkauskaite, Dagmar Volkmer, Y. Shigeyama, J. Schedel, G. Pap, U. Müller-Ladner, I. Meinecke, D. Alexander, R. Gay, S. Drynda, W. Neumann, B. Michel, W. Aicher, S. Gay, T. Pap (2005)
Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts.
Arthritis and rheumatism, 52 7
T. Aigner, E. Bartnik, F. Sohler, R. Zimmer (2004)
Functional Genomics of Osteoarthritis: On the Way to Evaluate Disease Hypotheses
Clinical Orthopaedics and Related Research, 1
Yufeng Dong, D. Soung, E. Schwarz, R. O’Keefe, H. Drissi (2006)
Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor
Journal of Cellular Physiology, 208
N. Taniguchi, K. Kawahara, K. Yone, T. Hashiguchi, M. Yamakuchi, M. Goto, Keiichi Inoue, S. Yamada, K. Ijiri, S. Matsunaga, T. Nakajima, S. Komiya, I. Maruyama (2003)
High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine.
Arthritis and rheumatism, 48 4
B Vandooren, T Cantaert, MJ van Lierop, E Bos, L De Rycke, EM Veys, F De Keyser, B Bresnihan, FP Luyten, PC Verdonk, PP Tak, AH Boots, D Baeten (2008)
Ann Rheum Dis
Katarzyna Piróg-Garcia, R. Meadows, L. Knowles, D. Heinegård, D. Thornton, K. Kadler, R. Boot-Handford, M. Briggs (2007)
Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP.
Human molecular genetics, 16 17
K. Ijiri, L. Zerbini, Hai-bing Peng, R. Correa, B. Lu, N. Walsh, Yani Zhao, N. Taniguchi, X. Huang, H. Otu, Hong Wang, Jian Wang, S. Komiya, P. Ducy, Mahboob Rahman, R. Flavell, E. Gravallese, P. Oettgen, T. Libermann, M. Goldring (2005)
A Novel Role for GADD45β as a Mediator of MMP-13 Gene Expression during Chondrocyte Terminal Differentiation*
Journal of Biological Chemistry, 280
Jennifer Lee, J. Fitzgerald, Michael Dimicco, A. Grodzinsky (2005)
Mechanical injury of cartilage explants causes specific time-dependent changes in chondrocyte gene expression.
Arthritis and rheumatism, 52 8
AM Valdes, TD Spector (2008)
The contribution of genes to osteoarthritis
Rheum Dis Clin North Am, 34
Xibin Wang, P. Manner, A. Horner, L. Shum, R. Tuan, G. Nuckolls (2004)
Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage.
Osteoarthritis and cartilage, 12 12
S. Tew, Y. Li, P. Pothacharoen, Lisa Tweats, R. Hawkins, T. Hardingham (2005)
Retroviral transduction with SOX9 enhances re-expression of the chondrocyte phenotype in passaged osteoarthritic human articular chondrocytes.
Osteoarthritis and cartilage, 13 1
V. Lefebvre, P. Smits (2005)
Transcriptional control of chondrocyte fate and differentiation.
Birth defects research. Part C, Embryo today : reviews, 75 3
(2008)
Focal adhesion kinase/ Src suppresses early chondrogenesis: central role of CCN2
R. Moskowitz (1992)
Osteoarthritis: Diagnosis and Medical/Surgical Management
Xiangwei Wu, Weibin Shi, Xu Cao (2007)
Multiplicity of BMP Signaling in Skeletal Development
Annals of the New York Academy of Sciences, 1116
F. Lago, C. Diéguez, J. Gómez-Reino, O. Gualillo (2007)
The emerging role of adipokines as mediators of inflammation and immune responses.
Cytokine & growth factor reviews, 18 3-4
Esmeralda Davidson, Peter Kraan, Wim Berg (2007)
TGF-β and osteoarthritis
Osteoarthritis and Cartilage, 15
Xuesong Chen, C. Macica, Ali Nasiri, A. Broadus (2008)
Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice.
Arthritis and rheumatism, 58 12
A. Caplan (2005)
Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics.
Tissue engineering, 11 7-8
R. Wilkins, J. Browning, J. Ellory (2000)
Surviving in a Matrix: Membrane Transport in Articular Chondrocytes
The Journal of Membrane Biology, 177
A. Dossumbekova, M. Anghelina, Shashi Madhavan, Lingli He, N. Quan, T. Knobloch, S. Agarwal (2007)
Biomechanical signals inhibit IKK activity to attenuate NF-kappaB transcription activity in inflamed chondrocytes.
Arthritis and rheumatism, 56 10
J. Dudhia (2005)
Aggrecan, aging and assembly in articular cartilage
Cellular and Molecular Life Sciences CMLS, 62
J. Lee, T. Ort, K. Ma, K. Picha, J. Carton, P. Marsters, L. Lohmander, F. Baribaud, X.-Y.R. Song, S. Blake (2007)
Resistin is elevated following traumatic joint injury and causes matrix degradation and release of inflammatory cytokines from articular cartilage in vitro.
Osteoarthritis and cartilage, 17 5
T. Ikeda, Satoru Kamekura, A. Mabuchi, I. Kou, Shoji Seki, T. Takato, Kozo Nakamura, H. Kawaguchi, S. Ikegawa, U. Chung (2004)
The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage.
Arthritis and rheumatism, 50 11
AJ Kvist, AE Johnson, M Mörgelin, E Gustafsson, E Bengtsson, K Lindblom, A Aszódi, R Fässler, T Sasaki, R Timpl, A Aspberg (2006)
Chondroitin sulfate perlecan enhances collagen fibril formation. Implications for perlecan chondrodysplasias
J Biol Chem, 281
G. Murphy, H. Nagase (2008)
Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair?
Nature Clinical Practice Rheumatology, 4
K. Ijiri, L. Zerbini, Hai-bing Peng, H. Otu, K. Tsuchimochi, M. Otero, C. Dragomir, N. Walsh, B. Bierbaum, D. Mattingly, G. Flandern, S. Komiya, T. Aigner, T. Libermann, M. Goldring (2008)
Differential expression of GADD45beta in normal and osteoarthritic cartilage: potential role in homeostasis of articular chondrocytes.
Arthritis and rheumatism, 58 7
H. Roach, Thomas Aigner, S. Söder, J. Haag, H. Welkerling (2007)
Pathobiology of osteoarthritis: pathomechanisms and potential therapeutic targets.
Current drug targets, 8 2
M. Francois, P. Richette, L. Tsagris, C. Fitting, C. Lemay, M. Benallaoua, K. Tahiri, M. Corvol (2006)
Activation of the peroxisome proliferator-activated receptor alpha pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes.
Arthritis and rheumatism, 54 4
Gillian Murphy, Meng-Huee Lee (2005)
What are the roles of metalloproteinases in cartilage and bone damage?
Annals of the Rheumatic Diseases, 64
M. Goldring, K. Tsuchimochi, K. Ijiri (2006)
The control of chondrogenesis
Journal of Cellular Biochemistry, 97
Krisztina Halász, Anja Kassner, M. Mörgelin, D. Heinegård (2007)
COMP Acts as a Catalyst in Collagen Fibrillogenesis*
Journal of Biological Chemistry, 282
W. Arend, M. Goldring (2008)
The development of anticytokine therapeutics for rheumatic diseases.
Arthritis and rheumatism, 58 2 Suppl
Y. Rengel, C. Ospelt, S. Gay (2007)
Proteinases in the joint: clinical relevance of proteinases in joint destruction
Arthritis Research & Therapy, 9
K. Bobacz, I. Sunk, J. Hofstaetter, L. Amoyo, C. Toma, S. Akira, T. Weichhart, M. Säemann, J. Smolen (2007)
Toll-like receptors and chondrocytes: the lipopolysaccharide-induced decrease in cartilage matrix synthesis is dependent on the presence of toll-like receptor 4 and antagonized by bone morphogenetic protein 7.
Arthritis and rheumatism, 56 6
G. Palmer, M. Aurrand-Lions, E. Contassot, D. Talabot‐Ayer, Dominique Ducrest-Gay, C. Vesin, V. Chobaz-Péclat, N. Busso, C. Gabay (2006)
Indirect Effects of Leptin Receptor Deficiency on Lymphocyte Populations and Immune Response in db/db Mice1
The Journal of Immunology, 177
E. Arner (2002)
Aggrecanase-mediated cartilage degradation.
Current opinion in pharmacology, 2 3
R. Lories, J. Peeters, A. Bakker, P. Tylzanowski, I. Derese, J. Schrooten, J. Thomas, Frank Luyten (2007)
Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice.
Arthritis and rheumatism, 56 12
M. Otero, R. Lago, R. Gómez, C. Diéguez, F. Lago, J. Gómez-Reino, O. Gualillo (2006)
Towards a pro-inflammatory and immunomodulatory emerging role of leptin.
Rheumatology, 45 8
Kohki Kawane, M. Ohtani, Keiko Miwa, Takuji Kizawa, Yoshiyuki Kanbara, Yoshichika Yoshioka, Hideki Yoshikawa, Shigekazu Nagata (2005)
Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis
Nature, 434
W. Koopman (1972)
Arthritis and allied conditions;: A textbook of rheumatology
D. Magne, C. Vinatier, M. Julien, P. Weiss, J. Guicheux (2005)
Mesenchymal stem cell therapy to rebuild cartilage.
Trends in molecular medicine, 11 11
Catherine Kuo, Wan-Ju Li, R. Mauck, R. Tuan (2006)
Cartilage tissue engineering: its potential and uses
Current Opinion in Rheumatology, 18
M. Ronzière, E. Aubert-Foucher, J. Gouttenoire, J. Bernaud, D. Herbage, F. Mallein-Gerin (2005)
Integrin α1β1 mediates collagen induction of MMP-13 expression in MC615 chondrocytes
Biochimica et Biophysica Acta, 1746
D. Burr (2004)
Anatomy and physiology of the mineralized tissues: role in the pathogenesis of osteoarthrosis.
Osteoarthritis and cartilage, 12 Suppl A
A. Pearle, C. Scanzello, SS George, L. Mandl, E. Dicarlo, Margaret Peterson, T. Sculco, M. Crow (2007)
Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis.
Osteoarthritis and cartilage, 15 5
J. Loughlin (2005)
Polymorphism in signal transduction is a major route through which osteoarthritis susceptibility is acting
Current Opinion in Rheumatology, 17
C Ruiz-Romero, V Calamia, J Mateos, V Carreira, M Martínez-Gomariz, M Fernández, FJ Blanco (2009)
Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance
Mol Cell Proteomics, 8
H. Dumond, N. Presle, B. Terlain, D. Mainard, D. Loeuille, P. Netter, P. Pottie (2003)
Evidence for a key role of leptin in osteoarthritis.
Arthritis and rheumatism, 48 11
P. Gregersen, T. Behrens (2006)
Genetics of autoimmune diseases — disorders of immune homeostasis
Nature Reviews Genetics, 7
Deike Varoga, Friedrich Paulsen, R. Mentlein, Jakob Fay, Bodo Kurz, R. Schütz, C. Wruck, M. Goldring, T. Pufe (2006)
TLR‐2‐mediated induction of vascular endothelial growth factor (VEGF) in cartilage in septic joint disease
The Journal of Pathology, 210
B. Vandooren, T. Cantaert, M. Borg, T. Noordenbos, R. Kuhlman, D. Gerlag, T. Bongartz, K. Reedquist, P. Tak, D. Baeten (2008)
Tumor necrosis factor alpha drives cadherin 11 expression in rheumatoid inflammation.
Arthritis and rheumatism, 58 10
A. Gilbert, M. Bursavich, S. Lombardi, K. Georgiadis, E. Reifenberg, C. Flannery, E. Morris (2008)
N-((8-hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2).
Bioorganic & medicinal chemistry letters, 18 24
G. Palmer, A. Steinert, A. Pascher, E. Gouze, J. Gouze, O. Betz, B. Johnstone, C. Evans, S. Ghivizzani (2005)
Gene-induced chondrogenesis of primary mesenchymal stem cells in vitro.
Molecular therapy : the journal of the American Society of Gene Therapy, 12 2
A. Kadri, Hang-Korng Ea, C. Bazille, D. Hannouche, F. Lioté, M. Cohen-Solal, M. Cohen-Solal (2008)
Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis.
Arthritis and rheumatism, 58 8
W. Berg (2001)
Lessons from animal models of osteoarthritis.
Current opinion in rheumatology, 13 5
Matthew Leighton, S. Nundlall, T. Starborg, R. Meadows, Farhana Suleman, L. Knowles, R. Wagener, D. Thornton, K. Kadler, R. Boot-Handford, M. Briggs (2007)
Decreased chondrocyte proliferation and dysregulated apoptosis in the cartilage growth plate are key features of a murine model of epiphyseal dysplasia caused by a matn3 mutation.
Human molecular genetics, 16 14
N. Lane, K. Lian, M. Nevitt, J. Zmuda, L. Lui, Jia Li, Jianmei Wang, M. Fontecha, Nanette Umblas, M. Rosenbach, P. Leon, M. Corr (2006)
Frizzled-related protein variants are risk factors for hip osteoarthritis.
Arthritis and rheumatism, 54 4
J. Pulai, Hong Chen, H. Im, Sanjay Kumar, C. Hanning, P. Hegde, R. Loeser (2005)
NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments1
The Journal of Immunology, 174
L. Neuhold, L. Killar, Weiguang Zhao, M. Sung., L. Warner, J. Kulik, James Turner, William Wu, C. Billinghurst, T. Meijers, A. Poole, P. Babij, L. Degennaro (2001)
Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice.
The Journal of clinical investigation, 107 1
S. Tat, J. Pelletier, D. Lajeunesse, H. Fahmi, Martin Lavigne, J. Martel-Pelletier (2008)
The differential expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) in human osteoarthritic subchondral bone osteoblasts is an indicator of the metabolic state of these disease cells.
Clinical and experimental rheumatology, 26 2
L. Ameye, M. Young (2006)
Animal models of osteoarthritis: lessons learned while seeking the ‘Holy Grail’
Current Opinion in Rheumatology, 18
J. Jukes, S. Both, A. Leusink, L. Sterk, C. Blitterswijk, J. Boer (2008)
Endochondral bone tissue engineering using embryonic stem cells
Proceedings of the National Academy of Sciences, 105
D. Baeten, P. Steenbakkers, A. Rijnders, A. Boots, E. Veys, F. Keyser (2004)
Detection of major histocompatibility complex/human cartilage gp-39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker.
Arthritis and rheumatism, 50 2
L. Alexopoulos, Gregory Williams, M. Upton, L. Setton, F. Guilak (2005)
Osteoarthritic changes in the biphasic mechanical properties of the chondrocyte pericellular matrix in articular cartilage.
Journal of biomechanics, 38 3
P. Burrage, Jonathan Huntington, M. Sporn, C. Brinckerhoff (2007)
Regulation of matrix metalloproteinase gene expression by a retinoid X receptor-specific ligand.
Arthritis and rheumatism, 56 3
B. Kurz, Angelika Lemke, J. Fay, T. Pufe, A. Grodzinsky, M. Schünke (2005)
Pathomechanisms of cartilage destruction by mechanical injury.
Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft, 187 5-6
W. Berg, P. Riel (2005)
Uncoupling of inflammation and destruction in rheumatoid arthritis: myth or reality?
Arthritis and rheumatism, 52 4
T. Aigner, H. Kim, H. Roach (2004)
Apoptosis in osteoarthritis.
Rheumatic diseases clinics of North America, 30 3
Tomoo Sato, K. Konomi, S. Yamasaki, S. Aratani, K. Tsuchimochi, M. Yokouchi, K. Masuko-hongo, N. Yagishita, Hiroshi Nakamura, S. Komiya, M. Beppu, H. Aoki, K. Nishioka, T. Nakajima (2006)
Comparative analysis of gene expression profiles in intact and damaged regions of human osteoarthritic cartilage.
Arthritis and rheumatism, 54 3
L. Goodrich, C. Hidaka, P. Robbins, C. Evans, A. Nixon (2007)
Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model.
The Journal of bone and joint surgery. British volume, 89 5
MB Goldring, LJ Sandell (2007)
OA, Inflammation and Degradation: A Continuum
E. Lubberts, M. Koenders, W. Berg (2004)
The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models
Arthritis Research & Therapy, 7
T. Pufe, Angelika Lemke, B. Kurz, W. Petersen, B. Tillmann, A. Grodzinsky, R. Mentlein (2004)
Mechanical overload induces VEGF in cartilage discs via hypoxia-inducible factor.
The American journal of pathology, 164 1
L. Sandell (2007)
Anabolic factors in degenerative joint disease.
Current drug targets, 8 2
H. Bukulmez, AL Matthews, CM Sullivan, C. Chen, M. Kraay, R. Elston, RW Moskowitz, V. Goldberg, M. Warman (2006)
Hip joint replacement surgery for idiopathic osteoarthritis aggregates in families
Arthritis Research & Therapy, 8
E. Lavallie, P. Chockalingam, L. Collins-Racie, Bethany Freeman, C. Keohan, M. Leitges, A. Dorner, E. Morris, M. Majumdar, M. Arai (2006)
Protein Kinase Cζ Is Up-regulated in Osteoarthritic Cartilage and Is Required for Activation of NF-κB by Tumor Necrosis Factor and Interleukin-1 in Articular Chondrocytes*
Journal of Biological Chemistry, 281
T. Imamura, C. Imamura, Y. Iwamoto, L. Sandell (2005)
Transcriptional Co-activators CREB-binding Protein/p300 Increase Chondrocyte Cd-rap Gene Expression by Multiple Mechanisms Including Sequestration of the Repressor CCAAT/Enhancer-binding Protein*
Journal of Biological Chemistry, 280
H. Stanton, F. Rogerson, C. East, S. Golub, K. Lawlor, Clare Meeker, C. Little, K. Last, P. Farmer, I. Campbell, A. Fourie, A. Fosang (2005)
ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro
Nature, 434
Y. Li, L. Xu, B. Olsen (2007)
Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease.
Osteoarthritis and cartilage, 15 10
Ling Yang, S. Carlson, D. McBurney, W. Horton (2005)
Multiple Signals Induce Endoplasmic Reticulum Stress in Both Primary and Immortalized Chondrocytes Resulting in Loss of Differentiation, Impaired Cell Growth, and Apoptosis*
Journal of Biological Chemistry, 280
廣畑和志, 松原司 (1985)
Cartilage in health and disease
L. Tetlow, D. Woolley (1998)
Comparative immunolocalization studies of collagenase 1 and collagenase 3 production in the rheumatoid lesion, and by human chondrocytes and synoviocytes in vitro.
British journal of rheumatology, 37 1
M. Otero, R. Lago, F. Lago, J. Reino, O. Gualillo (2005)
Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1
Arthritis Research & Therapy, 7
P. Lent, L. Grevers, A. Blom, O. Arntz, F. Loo, P. Kraan, S. Abdollahi-Roodsaz, G. Srikrishna, H. Freeze, A. Sloetjes, W. Nacken, T. Vogl, J. Roth, W. Berg (2008)
Stimulation of chondrocyte-mediated cartilage destruction by S100A8 in experimental murine arthritis.
Arthritis and rheumatism, 58 12
N. Verzijl, R. Bank, J. Tekoppele, J. DeGroot (2003)
AGEing and osteoarthritis: a different perspective
Current Opinion in Rheumatology, 15
Laura Bursell, A. Woods, Claudine James, D. Pala, A. Leask, F. Beier (2007)
Src kinase inhibition promotes the chondrocyte phenotype
Arthritis Research & Therapy, 9
William Wu, R. Billinghurst, I. Pidoux, J. Antoniou, D. Zukor, M. Tanzer, A. Poole (2002)
Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13.
Arthritis and rheumatism, 46 8
LC Tetlow, DJ Adlam, DE Woolley (2001)
Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage
Arthritis Rheum, 44
H. Barksby, S. Lea, P. Preshaw, John Taylor (2007)
The expanding family of interleukin‐1 cytokines and their role in destructive inflammatory disorders
Clinical & Experimental Immunology, 149
R. Loeser, C. Forsyth, A. Samarel, H. Im (2003)
Fibronectin Fragment Activation of Proline-rich Tyrosine Kinase PYK2 Mediates Integrin Signals Regulating Collagenase-3 Expression by Human Chondrocytes through a Protein Kinase C-dependent Pathway*
Journal of Biological Chemistry, 278
Lin Xu, Hai-bing Peng, S. Glasson, Peter Lee, Kenpan Hu, K. Ijiri, B. Olsen, M. Goldring, Yefu Li (2007)
Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis.
Arthritis and rheumatism, 56 8
T. John, B. Kohl, Ali Mobasheri, Wolfgang Ertel, M. Shakibaei (2007)
Interleukin-18 induces apoptosis in human articular chondrocytes.
Histology and histopathology, 22 5
M. Koenders, L. Joosten, W. Berg (2006)
Potential new targets in arthritis therapy: interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis
Annals of the Rheumatic Diseases, 65
A. Fraser, U. Fearon, R. Billinghurst, M. Ionescu, R. Reece, T. Barwick, P. Emery, A. Poole, D. Veale (2003)
Turnover of type II collagen and aggrecan in cartilage matrix at the onset of inflammatory arthritis in humans: relationship to mediators of systemic and local inflammation.
Arthritis and rheumatism, 48 11
M. Steenvoorden, T. Huizinga, N. Verzijl, R. Bank, H. Ronday, H. Luning, F. Lafeber, R. Toes, J. DeGroot (2006)
Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes.
Arthritis and rheumatism, 54 1
M. Benito, D. Veale, O. Fitzgerald, W. Berg, B. Bresnihan (2005)
Synovial tissue inflammation in early and late osteoarthritis
Annals of the Rheumatic Diseases, 64
Sheng-Ming Dai, Z. Shan, Kusuki Nishioka, K. Yudoh (2005)
Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal
Annals of the Rheumatic Diseases, 64
G. Schett, S. Hayer, J. Zwerina, K. Redlich, J. Smolen (2005)
Mechanisms of Disease: the link between RANKL and arthritic bone disease
Nature Clinical Practice Rheumatology, 1
Thomas Aigner, J. Haag, James Martin, J. Buckwalter (2007)
Osteoarthritis: aging of matrix and cells--going for a remedy.
Current drug targets, 8 2
S. Eleswarapu, Nic Leipzig, K. Athanasiou (2006)
Gene expression of single articular chondrocytes
Cell and Tissue Research, 327
S. Millward-Sadler, Donald Salter (2004)
Integrin-Dependent Signal Cascades in Chondrocyte Mechanotransduction
Annals of Biomedical Engineering, 32
T. Cawston, Amy Wilson (2006)
Understanding the role of tissue degrading enzymes and their inhibitors in development and disease.
Best practice & research. Clinical rheumatology, 20 5
H. Kautiainen, H. Badsha, I. Újfalussy, F. Skopouli, M. Mavrommati, R. Alten, W. Romanowski, Danuta Zarowny-Wierzbinska, B. Bresnihan, L. Knudsen, J. Jacobs, J. Lazovskis, Geraldo Rocha, D. Andersone, S. Rexhepi, T. Pincus (2009)
Arthritis Research & Therapy
Z. Fan, S. Söder, S. Oehler, Katrin Fundel, T. Aigner (2007)
Activation of interleukin-1 signaling cascades in normal and osteoarthritic articular cartilage.
The American journal of pathology, 171 3
R. Loeser, S. Chubinskaya, C. Pacione, H. Im (2005)
Basic fibroblast growth factor inhibits the anabolic activity of insulin-like growth factor 1 and osteogenic protein 1 in adult human articular chondrocytes.
Arthritis and rheumatism, 52 12
M. Vincenti, C. Brinckerhoff (2001)
Early response genes induced in chondrocytes stimulated with the inflammatory cytokine interleukin-1beta
Arthritis Research, 3
T. Haque, S. Nakada, R. Hamdy (2007)
A review of FGF18: Its expression, signaling pathways and possible functions during embryogenesis and post-natal development.
Histology and histopathology, 22 1
石田裕子, 向田直史, 近藤捻和 (2007)
皮膚創傷治癒とIL-1 receptor antagonist (IL-1ra)
, 47
WB van den Berg (2008)
Lessons from animal models of osteoarthritis
Curr Rheumatol Rep, 10
Mei Zhu, Dezhi Tang, Qiuqian Wu, Suyang Hao, Mo Chen, Chao Xie, R. Rosier, Regis O'Keefe, M. Zuscik, Di Chen (2009)
Activation of β‐Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis‐Like Phenotype in Adult β‐Catenin Conditional Activation Mice
Journal of Bone and Mineral Research, 24
C. Wiberg, A. Klatt, R. Wagener, M. Paulsson, J. Bateman, D. Heinegård, M. Mörgelin (2003)
Complexes of Matrilin-1 and Biglycan or Decorin Connect Collagen VI Microfibrils to Both Collagen II and Aggrecan*
Journal of Biological Chemistry, 278
A. Valdes, T. Spector (2009)
The contribution of genes to osteoarthritis.
The Medical clinics of North America, 93 1
B. Yoon, R. Pogue, D. Ovchinnikov, Isaac Yoshii, Y. Mishina, R. Behringer, K. Lyons (2006)
BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways
, 133
A. Pettit, H. Ji, D. Stechow, R. Müller, R. Müller, S. Goldring, Yongwon Choi, C. Benoist, E. Gravallese (2001)
TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis.
The American journal of pathology, 159 5
S. Cahue, L. Sharma, D. Dunlop, M. Ionescu, Jing Song, T. Lobanok, L. King, A. Poole (2007)
The ratio of type II collagen breakdown to synthesis and its relationship with the progression of knee osteoarthritis.
Osteoarthritis and cartilage, 15 7
S. Saito, S. Kondo, Shinji Mishima, Naoki Ishiguro, Yukiharu Hasegawa, Linda Sandell, Hisashi Iwata (2002)
Analysis of cartilage-derived retinoic-acid-sensitive protein (CD-RAP) in synovial fluid from patients with osteoarthritis and rheumatoid arthritis.
The Journal of bone and joint surgery. British volume, 84 7
CH Evans (2005)
Novel biological approaches to the intra-articular treatment of osteoarthritis
BioDrugs, 19
Hai-bing Peng, L. Tan, M. Osaki, Y. Zhan, K. Ijiri, K. Tsuchimochi, M. Otero, Hong Wang, B. Choy, F. Grall, Xuesong Gu, T. Libermann, P. Oettgen, M. Goldring (2008)
ESE‐1 is a potent repressor of type II collagen gene (COL2A1) transcription in human chondrocytes
Journal of Cellular Physiology, 215
F. Loo, J. Geurts, W. Berg (2006)
Gene therapy works in animal models of rheumatoid arthritis so what!
Current Rheumatology Reports, 8
Satoru Kamekura, Y. Kawasaki, K. Hoshi, Takashi Shimoaka, H. Chikuda, Z. Maruyama, T. Komori, Shingo Sato, S. Takeda, G. Karsenty, Kozo Nakamura, U. Chung, H. Kawaguchi (2006)
Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability.
Arthritis and rheumatism, 54 8
H. Kim, M. Cho, H. Choi, C. Yoon, J. Jhun, H. Oh, H. Kim (2006)
The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes.
Arthritis and rheumatism, 54 7
R. Borzì, I. Mazzetti, K. Marcu, A. Facchini (2004)
Chemokines in cartilage degradation.
Clinical orthopaedics and related research, 427 Suppl
JM Dayer, R Chicheportiche, C Juge-Aubry, C Meier (2006)
Adipose tissue has anti-inflammatory properties: focus on IL-1 receptor antagonist (IL-1Ra)
Ann N Y Acad Sci, 1069
Jerry Huang, Najam Kazmi, Mahidhar Durbhakula, T. Hering, J. Yoo, B. Johnstone (2005)
Chondrogenic potential of progenitor cells derived from human bone marrow and adipose tissue: A patient‐matched comparison
Journal of Orthopaedic Research, 23
T. Knobloch, Shashi Madhavan, Jin Nam, Suresh Agarwal, S. Agarwal (2008)
Regulation of chondrocytic gene expression by biomechanical signals.
Critical reviews in eukaryotic gene expression, 18 2
(2007)
TGFb and osteoarthritis. Osteoarthritis Cartilage
J. Deschner, C. Hofman, N. Piesco, S. Agarwal (2003)
Signal transduction by mechanical strain in chondrocytes
Current Opinion in Clinical Nutrition and Metabolic Care, 6
E. Lindqvist, K. Eberhardt, K. Bendtzen, D. Heinegård, T. Saxne (2004)
Prognostic laboratory markers of joint damage in rheumatoid arthritis
Annals of the Rheumatic Diseases, 64
R. Lories, F. Luyten (2005)
Bone morphogenetic protein signaling in joint homeostasis and disease.
Cytokine & growth factor reviews, 16 3
S. Goldring, M. Goldring (2007)
Eating bone or adding it: the Wnt pathway decides
Nature Medicine, 13
S. Su, C. Tsai, C. Lee, D. Salter, Herng‐Sheng Lee (2005)
Expression and regulation of Toll-like receptor 2 by IL-1β and fibronectin fragments in human articular chondrocytes
Osteoarthritis and Cartilage, 13
A. Valdes, M. Oene, D. Hart, G. Surdulescu, J. Loughlin, M. Doherty, T. Spector (2006)
Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women.
Arthritis and rheumatism, 54 2
L. Sandell, X. Xing, Carl Franz, S. Davies, Li-Wei Chang, D. Patra (2008)
Exuberant expression of chemokine genes by adult human articular chondrocytes in response to IL-1beta.
Osteoarthritis and cartilage, 16 12
Y. Tamamura, T. Otani, N. Kanatani, E. Koyama, J. Kitagaki, T. Komori, Yoshihiko Yamada, F. Costantini, S. Wakisaka, M. Pacifici, M. Iwamoto, M. Enomoto-Iwamoto (2005)
Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification.
The Journal of biological chemistry, 280 19
D. Plumb, V. Dhir, Aleksandr Mironov, L. Ferrara, R. Poulsom, K. Kadler, D. Thornton, M. Briggs, R. Boot-Handford (2007)
Collagen XXVII Is Developmentally Regulated and Forms Thin Fibrillar Structures Distinct from Those of Classical Vertebrate Fibrillar Collagens*
Journal of Biological Chemistry, 282
A. Rowan, P. Koshy, W. Shingleton, B. Degnan, J. Heath, A. Vernallis, J. Spaull, P. Life, K. Hudson, T. Cawston (2001)
Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown.
Arthritis and rheumatism, 44 7
Jesse Otero, S. Dai, D. Foglia, Muhammad Alhawagri, J. Vacher, M. Pasparakis, Y. Abu-Amer (2008)
Defective Osteoclastogenesis by IKKβ-null Precursors Is a Result of Receptor Activator of NF-κB Ligand (RANKL)-induced JNK-dependent Apoptosis and Impaired Differentiation*
Journal of Biological Chemistry, 283
L. Tetlow, L. Tetlow, D. Adlam, D. Woolley (2001)
Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes.
Arthritis and rheumatism, 44 3
F. Guilak, B. Fermor, F. Keefe, V. Kraus, S. Olson, D. Pisetsky, L. Setton, J. Weinberg (2004)
The role of biomechanics and inflammation in cartilage injury and repair.
Clinical orthopaedics and related research, 423
S. Cheng, H. Afif, J. Martel-Pelletier, J. Pelletier, Xinfang Li, K. Farrajota, M. Lavigne, H. Fahmi (2004)
Activation of Peroxisome Proliferator-activated Receptor γ Inhibits Interleukin-1β-induced Membrane-associated Prostaglandin E2 Synthase-1 Expression in Human Synovial Fibroblasts by Interfering with Egr-1*
Journal of Biological Chemistry, 279
D. Hunter, Jiang Li, M. Lavalley, D. Bauer, M. Nevitt, J. DeGroot, R. Poole, D. Eyre, A. Guermazi, D. Gale, D. Felson (2007)
Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study
Arthritis Research & Therapy, 9
P. Koshy, N. Henderson, C. Logan, P. Life, T. Cawston, A. Rowan (2002)
Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines
Annals of the Rheumatic Diseases, 61
H. Kizawa, I. Kou, A. Iida, A. Sudo, Y. Miyamoto, A. Fukuda, A. Mabuchi, A. Kotani, A. Kawakami, Seizo Yamamoto, A. Uchida, Kozo Nakamura, K. Notoya, Yusuke Nakamura, S. Ikegawa (2005)
An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis
Nature Genetics, 37
H. Roach, N. Yamada, Kelvin Cheung, S. Tilley, N. Clarke, R. Oreffo, S. Kokubun, F. Bronner (2005)
Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions.
Arthritis and rheumatism, 52 10
J. Pulai, Hong Chen, Hee-Jeong Im, Sanjay Kumar, Charles Hanning, Priti Hegde, Richard Loeser (2005)
NF-kappa B mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments.
Journal of immunology, 174 9
(2008)
Key regulatory molecules of cartilage destruction in rheumatoid arthritis: an in vitro study
J. Zwerina, K. Redlich, K. Polzer, L. Joosten, G. Krönke, J. Distler, A. Hess, N. Pundt, T. Pap, O. Hoffmann, J. Gasser, C. Scheinecker, J. Smolen, W. Berg, G. Schett (2007)
TNF-induced structural joint damage is mediated by IL-1
Proceedings of the National Academy of Sciences, 104
JH Lee, T Ort, K Ma, K Picha, J Carton, PA Marsters, LS Lohmander, F Baribaud, XY Song, S Blake (2008)
Osteoarthritis Cartilage
V. Grishko, R. Ho, G. Wilson, A. Pearsall (2009)
Diminished mitochondrial DNA integrity and repair capacity in OA chondrocytes.
Osteoarthritis and cartilage, 17 1
David Walsh, C. Bonnet, E. Turner, D. Wilson, M. Situ, D. McWilliams (2007)
Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis.
Osteoarthritis and cartilage, 15 7
T. Aigner, Katrin Fundel, J. Saas, P. Gebhard, J. Haag, Tilo Weiss, A. Zien, F. Obermayr, R. Zimmer, E. Bartnik (2006)
Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis.
Arthritis and rheumatism, 54 11
Chuzhao Lin, Richard Mcgough, B. Aswad, J. Block, R. Terek (2004)
Hypoxia induces HIF‐1α and VEGF expression in chondrosarcoma cells and chondrocytes
Journal of Orthopaedic Research, 22
Christina Cheng, Evan Conte, Nancy Pleshko-Camacho, C. Hidaka (2007)
Differences in matrix accumulation and hypertrophy in superficial and deep zone chondrocytes are controlled by bone morphogenetic protein.
Matrix biology : journal of the International Society for Matrix Biology, 26 7
E. Tchetina, Ginette Squires, A. Poole (2005)
Increased type II collagen degradation and very early focal cartilage degeneration is associated with upregulation of chondrocyte differentiation related genes in early human articular cartilage lesions.
The Journal of rheumatology, 32 5
S. Firestein (2004)
Kelley's Textbook of Rheumatology
MB Goldring, SR Goldring (2007)
Osteoarthritis
J Cell Physiol, 213
B. Hopwood, A. Tsykin, D. Findlay, N. Fazzalari (2007)
Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-β/bone morphogenic protein signalling
Arthritis Research & Therapy, 9
L. Joosten, M. Netea, Soohyun Kim, D. Yoon, B. Oppers-Walgreen, T. Radstake, P. Barrera, F. Loo, C. Dinarello, W. Berg (2006)
IL-32, a proinflammatory cytokine in rheumatoid arthritis.
Proceedings of the National Academy of Sciences of the United States of America, 103 9
D. Kane, L. Jensen, S. Grehan, A. Whitehead, B. Bresnihan, O. FitzGerald (2004)
Quantitation of metalloproteinase gene expression in rheumatoid and psoriatic arthritis synovial tissue distal and proximal to the cartilage-pannus junction.
The Journal of rheumatology, 31 7
B. Bau, P. Gebhard, J. Haag, T. Knorr, E. Bartnik, T. Aigner (2002)
Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro.
Arthritis and rheumatism, 46 10
Hajime Komuro, T. Olee, Klaus Khn, J. Quach, D. Brinson, Alexander Shikhman, J. Valbracht, Lilo Creighton-Achermann, Martin Lotz (2001)
The osteoprotegerin/receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand system in cartilage.
Arthritis and rheumatism, 44 12
C. Popa, M. Netea, T. Radstake, P. Riel, P. Barrera, J. Meer (2005)
Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis
Annals of the Rheumatic Diseases, 64
T. Aigner, P. Gebhard, E. Schmid, B. Bau, V. Harley, E. Pöschl (2003)
SOX9 expression does not correlate with type II collagen expression in adult articular chondrocytes.
Matrix biology : journal of the International Society for Matrix Biology, 22 4
Shashi Madhavan, M. Anghelina, D. Sjostrom, A. Dossumbekova, D. Guttridge, S. Agarwal (2007)
Biomechanical Signals Suppress TAK1 Activation to Inhibit NF-κB Transcriptional Activation in Fibrochondrocytes1
The Journal of Immunology, 179
S. Bos, P. Slagboom, I. Meulenbelt (2008)
New insights into osteoarthritis: early developmental features of an ageing-related disease
Current Opinion in Rheumatology, 20
M. Attur, M. Dave, K. Tsunoyama, M. Akamatsu, M. Kobori, J. Miki, Steven Abramson, M. Katoh, Ashok Amin (2002)
"A system biology" approach to bioinformatics and functional genomics in complex human diseases: arthritis.
Current issues in molecular biology, 4 4
D. Cecil, R. Terkeltaub (2008)
Transamidation by Transglutaminase 2 Transforms S100A11 Calgranulin into a Procatabolic Cytokine for Chondrocytes1
The Journal of Immunology, 180
A. Mobasheri, C. Bondy, K. Moley, A. Mendes, S. Rosa, S. Richardson, J. Hoyland, R. Barrett-Jolley, M. Shakibaei (2008)
Facilitative glucose transporters in articular chondrocytes. Expression, distribution and functional regulation of GLUT isoforms by hypoxia, hypoxia mimetics, growth factors and pro-inflammatory cytokines.
Advances in anatomy, embryology, and cell biology, 200
H. Barksby, J. Milner, A. Patterson, N. Peake, Wang Hui, T. Robson, R. Lakey, J. Middleton, T. Cawston, C. Richards, A. Rowan (2006)
Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: implications for cartilage degradation in arthritis.
Arthritis and rheumatism, 54 10
P. Lent, A. Blom, L. Grevers, A. Sloetjes, W. Berg (2006)
Toll-like receptor 4 induced FcγR expression potentiates early onset of joint inflammation and cartilage destruction during immune complex arthritis: Toll-like receptor 4 largely regulates FcγR expression by interleukin 10
Annals of the Rheumatic Diseases, 66
E. Dayer, J. Dayer, P. Roux‐Lombard (2007)
Primer: the practical use of biological markers of rheumatic and systemic inflammatory diseases
Nature Clinical Practice Rheumatology, 3
Kenneth Brandt, Paul Dieppe, Eric Radin (2009)
Etiopathogenesis of osteoarthritis.
The Medical clinics of North America, 93 1
Q. Zhang, Wang Hui, G. Litherland, M. Barter, R. Davidson, C. Darrah, S. Donell, Ian Clark, T. Cawston, John Robinson, A. Rowan, D. Young (2008)
Differential Toll-like receptor-dependent collagenase expression in chondrocytes
Annals of the Rheumatic Diseases, 67
Matthew Whiteman, J.P.E. Spencer, J.P.E. Spencer, Yi-Zhun Zhu, J. Armstrong, J. Schantz (2006)
Peroxynitrite-modified collagen-II induces p38/ERK and NF-kappaB-dependent synthesis of prostaglandin E2 and nitric oxide in chondrogenically differentiated mesenchymal progenitor cells.
Osteoarthritis and cartilage, 14 5
(2008)
Endochondral bone tissue engineering using embry Available online http://arthritis-research.com/content/11/3/224 Page 15 of 16 (page number not for citation purposes) onic stem cells
H. Drissi, M. Zuscik, R. Rosier, R. O’Keefe (2005)
Transcriptional regulation of chondrocyte maturation: potential involvement of transcription factors in OA pathogenesis.
Molecular aspects of medicine, 26 3
A. Mobasheri, C. Bondy, K. Moley, A. Mendes, S. Rosa, S. Richardson, J. Hoyland, R. Barrett-Jolley, M. Shakibaei (2008)
Facilitative Glucose Transporters in Articular Chondrocytes
N. Fukui, Y. Ikeda, Toshiyuki Ohnuki, N. Tanaka, Atsuhiko Hikita, H. Mitomi, Toshihito Mori, T. Juji, Y. Katsuragawa, Seizo Yamamoto, M. Sawabe, S. Yamane, R. Suzuki, L. Sandell, T. Ochi (2008)
Regional differences in chondrocyte metabolism in osteoarthritis: a detailed analysis by laser capture microdissection.
Arthritis and rheumatism, 58 1
Tommi Tallheden, James Dennis, D. Lennon, E. Sjögren‐Jansson, Arnold Caplan, Anders Lindahl (2003)
Phenotypic Plasticity of Human Articular Chondrocytes
The Journal of Bone & Joint Surgery, 85
P. Kraan, Wim Berg (2007)
Osteophytes: relevance and biology.
Osteoarthritis and cartilage, 15 3
C. Hidaka, M. Goldring (2008)
Regulatory Mechanisms of Chondrogenesis and Implications for Understanding Articular Cartilage Homeostasis
Current Rheumatology Reviews, 4
Kenneth Brandt, Paul Dieppe, Eric Radin (2008)
Etiopathogenesis of osteoarthritis.
Rheumatic diseases clinics of North America, 34 3
K. Kishimoto, R. Kitazawa, M. Kurosaka, S. Maeda, S. Kitazawa (2006)
Expression profile of genes related to osteoclastogenesis in mouse growth plate and articular cartilage
Histochemistry and Cell Biology, 125
A. Kvist, Anna Johnson, M. Mörgelin, E. Gustafsson, E. Bengtsson, K. Lindblom, A. Aszódi, R. Fässler, Takako Sasaki, R. Timpl, A. Aspberg (2006)
Chondroitin Sulfate Perlecan Enhances Collagen Fibril Formation
Journal of Biological Chemistry, 281
C. Overall, C. Blobel (2007)
In search of partners: linking extracellular proteases to substrates
Nature Reviews Molecular Cell Biology, 8
J. Robins, N. Akeno, A. Mukherjee, Ravi Dalal, B. Aronow, P. Koopman, T. Clemens (2005)
Hypoxia induces chondrocyte-specific gene expression in mesenchymal cells in association with transcriptional activation of Sox9.
Bone, 37 3
M. Ruocco, S. Maeda, Jin Park, T. Lawrence, L. Hsu, Yixue Cao, G. Schett, E. Wagner, M. Karin (2005)
IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss
The Journal of Experimental Medicine, 201
P. Lent, L. Grevers, A. Blom, A. Sloetjes, J. Mort, T. Vogl, W. Nacken, W. Berg, J. Roth (2007)
Myeloid-related proteins S100A8/S100A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis
Annals of the Rheumatic Diseases, 67
John Sandy (2006)
A contentious issue finds some clarity: on the independent and complementary roles of aggrecanase activity and MMP activity in human joint aggrecanolysis.
Osteoarthritis and cartilage, 14 2
J. Dayer (2004)
The process of identifying and understanding cytokines: from basic studies to treating rheumatic diseases.
Best practice & research. Clinical rheumatology, 18 1
David Lee, H. Kiener, S. Agarwal, E. Noss, G. Watts, O. Chisaka, M. Takeichi, M. Brenner (2007)
Cadherin-11 in Synovial Lining Formation and Pathology in Arthritis
Science, 315
D. Diarra, M. Stolina, K. Polzer, J. Zwerina, M. Ominsky, D. Dwyer, A. Korb, J. Smolen, M. Hoffmann, C. Scheinecker, D. Heide, R. Landewé, D. Lacey, W. Richards, G. Schett (2007)
Dickkopf-1 is a master regulator of joint remodeling
Nature Medicine, 13
R. Smeets, Sharon Veenbergen, O. Arntz, M. Bennink, L. Joosten, W. Berg, F. Loo (2006)
A novel role for suppressor of cytokine signaling 3 in cartilage destruction via induction of chondrocyte desensitization toward insulin-like growth factor.
Arthritis and rheumatism, 54 5
L. Šenolt, D. Housa, Z. Vernerová, T. Jirásek, R. Svobodová, D. Veigl, K. Anderlová, U. Müller-Ladner, K. Pavelka, M. Haluzík (2006)
Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum
Annals of the Rheumatic Diseases, 66
L. Kevorkian, D. Young, C. Darrah, S. Donell, L. Shepstone, S. Porter, S. Brockbank, D. Edwards, A. Parker, I. Clark (2004)
Expression profiling of metalloproteinases and their inhibitors in cartilage.
Arthritis and rheumatism, 50 1
Y. Henrotin, S. Addison, V. Kraus, M. Deberg (2007)
Type II collagen markers in osteoarthritis: what do they indicate?
Current Opinion in Rheumatology, 19
Xinfang Li, H. Afif, S. Cheng, J. Martel-Pelletier, J. Pelletier, P. Ranger, H. Fahmi (2005)
Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes.
The Journal of rheumatology, 32 5
Y. Zhou, S. Millward-Sadler, H. Lin, H. Robinson, M. Goldring, D. Salter, G. Nuki (2007)
Evidence for JNK-dependent up-regulation of proteoglycan synthesis and for activation of JNK1 following cyclical mechanical stimulation in a human chondrocyte culture model.
Osteoarthritis and cartilage, 15 8
P. Fanning, Gregory Emkey, Robert Smith, A. Grodzinsky, N. Szasz, S. Trippel (2003)
Mechanical Regulation of Mitogen-activated Protein Kinase Signaling in Articular Cartilage*
Journal of Biological Chemistry, 278
J. Rousseau, P. Delmas (2007)
Biological markers in osteoarthritis
Nature Clinical Practice Rheumatology, 3
A. Mobasheri, S. Richardson, R. Mobasheri, M. Shakibaei, J. Hoyland (2005)
Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes.
Histology and histopathology, 20 4
L. Ramage, Marc‐André Martel, Giles Hardingham, Donald Salter (2008)
NMDA receptor expression and activity in osteoarthritic human articular chondrocytes.
Osteoarthritis and cartilage, 16 12
James Martin, T. Brown, A. Heiner, J. Buckwalter, R. Smith (2004)
Chondrocyte Senescence, Joint Loading and Osteoarthritis
Clinical Orthopaedics and Related Research, 1
K. Masuko-hongo, F. Berenbaum, L. Humbert, C. Salvat, M. Goldring, S. Thirion (2004)
Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways.
Arthritis and rheumatism, 50 9
H. Helminen, A. Säämänen, H. Salminen, M. Hyttinen (2002)
Transgenic mouse models for studying the role of cartilage macromolecules in osteoarthritis.
Rheumatology, 41 8
S. Glasson, T. Blanchet, E. Morris (2007)
The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse.
Osteoarthritis and cartilage, 15 9
(2007)
Aging, inflammation, and altered chondrocyte differentiation in articular cartilage calcification and osteoarthritis
I. Meulenbelt, J. Min, S. Bos, N. Riyazi, J. Houwing-Duistermaat, H. Wijk, H. Kroon, M. Nakajima, S. Ikegawa, A. Uitterlinden, J. Meurs, W. Deure, T. Visser, A. Seymour, N. Lakenberg, R. Breggen, D. Kremer, C. Duijn, M. Kloppenburg, J. Loughlin, P. Slagboom (2008)
Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis.
Human molecular genetics, 17 12
H. Barksby, Wang Hui, I. Wappler, Heiko Peters, J. Milner, Carl Richards, T. Cawston, A. Rowan (2006)
Interleukin-1 in combination with oncostatin M up-regulates multiple genes in chondrocytes: implications for cartilage destruction and repair.
Arthritis and rheumatism, 54 2
J. Loughlin, B. Dowling, K. Chapman, Lucy Marcelline, Z. Mustafa, L. Southam, Athena Ferreira, C. Ciesielski, D. Carson, M. Corr (2004)
Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females.
Proceedings of the National Academy of Sciences of the United States of America, 101 26
M. Hermansson, Y. Sawaji, M. Bolton, S. Alexander, A. Wallace, S. Begum, R. Wait, J. Saklatvala (2004)
Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin βA (Activin A), a Regulatory Molecule for Chondrocytes*
Journal of Biological Chemistry, 279
F. Barry, J. Murphy (2004)
Mesenchymal stem cells: clinical applications and biological characterization.
The international journal of biochemistry & cell biology, 36 4
Nan Zhong, R. Gersch, M. Hadjiargyrou (2006)
Wnt signaling activation during bone regeneration and the role of Dishevelled in chondrocyte proliferation and differentiation.
Bone, 39 1
E. Olivotto, R. Borzì, R. Vitellozzi, S. Pagani, A. Facchini, M. Battistelli, M. Penzo, Xiang Li, F. Flamigni, Jun Li, E. Falcieri, A. Facchini, K. Marcu (2008)
Differential requirements for IKKalpha and IKKbeta in the differentiation of primary human osteoarthritic chondrocytes.
Arthritis and rheumatism, 58 1
A. Plaas, B. Osborn, Y. Yoshihara, Y. Bai, T. Bloom, F. Nelson, K. Mikecz, J. Sandy (2007)
Aggrecanolysis in human osteoarthritis: confocal localization and biochemical characterization of ADAMTS5-hyaluronan complexes in articular cartilages.
Osteoarthritis and cartilage, 15 7
Zachary Healy, N. Lee, Xiangqun Gao, M. Goldring, P. Talalay, T. Kensler, K. Konstantopoulos (2005)
Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis.
Proceedings of the National Academy of Sciences of the United States of America, 102 39
S. Sahebjam, R. Khokha, J. Mort (2007)
Increased collagen and aggrecan degradation with age in the joints of Timp3(-/-) mice.
Arthritis and rheumatism, 56 3
Guang Zhou, Qiping Zheng, Feyza Engin, Elda Munivez, Yuqing Chen, Eiman Sebald, D. Krakow, Brendan Lee (2006)
Dominance of SOX9 function over RUNX2 during skeletogenesis
Proceedings of the National Academy of Sciences, 103
M. Goldring (2006)
Are bone morphogenetic proteins effective inducers of cartilage repair? Ex vivo transduction of muscle-derived stem cells.
Arthritis and rheumatism, 54 2
R. Dreier, S. Grässel, S. Fuchs, J. Schaumburger, P. Bruckner (2004)
Pro-MMP-9 is a specific macrophage product and is activated by osteoarthritic chondrocytes via MMP-3 or a MT1-MMP/MMP-13 cascade.
Experimental cell research, 297 2
R. Kuroda, A. Usas, S. Kubo, K. Corsi, Hairong Peng, T. Rose, J. Cummins, Freddie Fu, J. Huard (2006)
Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells.
Arthritis and rheumatism, 54 2
A. Valdes, John Loughlin, M. Oene, K. Chapman, G. Surdulescu, M. Doherty, T. Spector (2007)
Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee.
Arthritis and rheumatism, 56 1
B. Vandooren, B. Vandooren, T. Cantaert, M. Lierop, E. Bos, L. Rycke, E. Veys, F. Keyser, B. Bresnihan, F. Luyten, Peter Verdonk, P. Tak, A. Boots, D. Baeten, D. Baeten (2008)
Melanoma inhibitory activity, a biomarker related to chondrocyte anabolism, is reversibly suppressed by proinflammatory cytokines in rheumatoid arthritis
Annals of the Rheumatic Diseases, 68
R. Palumbo, B. Galvez, Tobias Pusterla, F. Marchis, G. Cossu, K. Marcu, M. Bianchi (2007)
Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-κB activation
The Journal of Cell Biology, 179
David Eyre, MaryAnn Weis, Jiann-Jiu Wu (2006)
Articular cartilage collagen: an irreplaceable framework?
European cells & materials, 12
N. Tabassi, P. Garnero (2007)
Monitoring cartilage turnover
Current Rheumatology Reports, 9
N. Taniguchi, Kenji Yoshida, Tatsuo Ito, M. Tsuda, Y. Mishima, T. Furumatsu, L. Ronfani, K. Abeyama, K. Kawahara, S. Komiya, I. Maruyama, M. Lotz, M. Bianchi, H. Asahara (2007)
Stage-Specific Secretion of HMGB1 in Cartilage Regulates Endochondral Ossification
Molecular and Cellular Biology, 27
L. Haglund, S. Bernier, P. Onnerfjord, A. Recklies (2008)
Proteomic analysis of the LPS-induced stress response in rat chondrocytes reveals induction of innate immune response components in articular cartilage.
Matrix biology : journal of the International Society for Matrix Biology, 27 2
R. Loeser (2006)
Molecular mechanisms of cartilage destruction: mechanics, inflammatory mediators, and aging collide.
Arthritis and rheumatism, 54 5
J. Fitzgerald, Moonsoo Jin, D. Dean, D. Wood, M. Zheng, A. Grodzinsky (2004)
Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP*
Journal of Biological Chemistry, 279
R. Yammani, C. Carlson, A. Bresnick, R. Loeser (2006)
Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products.
Arthritis and rheumatism, 54 9

Publisher: Pubmed Central
Copyright: Copyright © 2009 BioMed Central Ltd
ISSN: 1478-6354
eISSN: 1478-6362
DOI: 10.1186/ar2592
Publisher site: See Article on Publisher Site

Abstract

Available online http://arthritis-research.com/content/11/3/224 Review 1 2,3 Mary B Goldring and Kenneth B Marcu Research Division, Hospital for Special Surgery, affiliated with Weill College of Medicine of Cornell University, Caspary Research Building, 535 E. 70th Street, New York, NY 10021, USA Biochemistry and Cell Biology Department, Stony Brook University, Life Sciences Rm #330, Stony Brook, NY 11794, USA Centro Ricerca Biomedica Applicata, S. Orsola-Malpighi University Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy Corresponding author: Mary B Goldring, [email protected] Published: 19 May 2009 Arthritis Research & Therapy 2009, 11:224 (doi:10.1186/ar2592) This article is online at http://arthritis-research.com/content/11/3/224 © 2009 BioMed Central Ltd Abstract certain matrix proteins. During aging and joint disease, this equilibrium is disrupted and the rate of loss of collagens and As the cellular component of articular cartilage, chondrocytes are proteoglycans from the matrix may exceed the rate of responsible for maintaining in a low-turnover state the unique deposition of newly synthesized molecules. Originally con- composition and organization of the matrix that was determined during embryonic and postnatal development. In joint diseases, sidered an inert tissue, cartilage is now considered to cartilage homeostasis is disrupted by mechanisms that are driven respond to extrinsic factors that regulate gene expression by combinations of biological mediators that vary according to the and protein synthesis in chondrocytes. Numerous studies in disease process, including contributions from other joint tissues. In vitro and in vivo during the last two decades have confirmed osteoarthritis (OA), biomechanical stimuli predominate with up- that articular chondrocytes are able to respond to mechanical regulation of both catabolic and anabolic cytokines and recapitula- tion of developmental phenotypes, whereas in rheumatoid arthritis injury, joint instability due to genetic factors, and biological (RA), inflammation and catabolism drive cartilage loss. In vitro stimuli such as cytokines and growth and differentiation studies in chondrocytes have elucidated signaling pathways and factors that contribute to structural changes in the surround- transcription factors that orchestrate specific functions that promote ing cartilage matrix [1]. Mechanical influences on chondro- cartilage damage in both OA and RA. Thus, understanding how the cyte function are considered to be important in the patho- adult articular chondrocyte functions within its unique environment genesis of osteoarthritis (OA), but chondrocyte responses to will aid in the development of rational strategies to protect cartilage from damage resulting from joint disease. This review will cover molecular signals may vary in different regions, including the current knowledge about the specific cellular and biochemical calcified cartilage, and also occur at different stages over a mechanisms that regulate cartilage homeostasis and pathology. long time course (Figure 1). In rheumatoid arthritis (RA), the inflamed synovium is the major source of cytokines and Introduction proteinases that mediate cartilage destruction in areas Adult articular cartilage is an avascular tissue composed of a adjacent to the proliferating synovial pannus (Figure 2) [2]. specialized matrix of collagens, proteoglycans, and non- However, the basic cellular mechanisms regulating chondro- collagen proteins, in which chondrocytes constitute the cyte responses are very different in OA and RA. Moreover, unique cellular component. Although chondrocytes in this mechanistic insights from in vitro studies ideally should be context do not normally divide, they are assumed to maintain interpreted in light of direct analysis of human cartilage and the extracellular matrix (ECM) by low-turnover replacement of other joint tissues and studies in experimental models, inclu- ADAM = a disintegrin and metalloproteinase; ADAMTS = a disintegrin and metalloproteinase with thrombospondin-1 domains; AGE = advanced glycation end product; CD-RAP = cartilage-derived retinoic acid-sensitive protein; COL2A1 = collagen, type II, alpha 1; COMP = cartilage oligomeric matrix protein; COX-2 = cyclooxygenase 2; DDR-2 = discoidin domain receptor 2; DZC = deep zone chondrocyte; ECM = extracellular matrix; ERK = extracellular signal-regulated kinase; FRZB = frizzled-related protein 3; GADD45β = growth arrest and DNA damage 45 beta; GLUT = glucose transporter protein; HIF-1α = hypoxia-inducible factor-1-alpha; HMGB1 = high-mobility group protein 1; hTNFtg = human tumor necrosis factor transgenic; IGF-1 = insulin-like growth factor 1; Ihh = Indian hedgehog; IKK = IκB kinase; IL = interleukin; JNK = c-jun N-terminal kinase; MAPK = mitogen-activated protein kinase; MIA = melanoma inhibitory activity; MMP = matrix metalloproteinase; mPGES-1 = microsomal prostaglandin E synthase 1; MSC = mesenchymal stem cell; MZC = middle zone chondrocyte; NF-κB = nuclear factor-kappa-B; NO = nitric oxide; OA = osteoarthritis; PGE = prostaglandin E; PPAR = peroxisome proliferator-activated receptor; RA = rheumatoid arthritis; RAGE = receptor for advanced glycation end products; RANK = receptor activator of nuclear factor-kappa-B; RANKL = receptor activator of nuclear factor-kappa-B ligand; ROS = reactive oxygen species; SMAD = signal-transducing mothers against decapentaplegic; SOCS = suppressor of cytokine signaling; SZC = superficial zone chondrocyte; TGF-β = transforming growth factor-beta; TLR = Toll-like receptor; TNF-α = tumor necrosis factor-alpha; VEGF = vascular endothelial growth factor. Page 1 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu Figure 1 Cellular interactions in cartilage destruction in osteoarthritis. This scheme represents the destruction of the cartilage due to mechanical loading and biological factors. The induction of stress-induced intracellular signals, catabolic cytokines, including interleukin-1 (IL-1) and tumor necrosis factor- alpha (TNF-α), chemokines, and other inflammatory mediators produced by synovial cells and chondrocytes results in the upregulation of cartilage- degrading enzymes of the matrix metalloproteinase (MMP) and ADAMTS families. Matrix degradation products can feedback regulate these cellular events. Anabolic factors, including bone morphogenetic proteins (BMPs) and transforming growth factor-beta (TGF-β), may also be upregulated and participate in osteophyte formation. In addition to matrix loss, evidence of earlier changes, such as chondrocyte proliferation and hypertrophy, increased cartilage calcification with tidemark advancement, and microfractures with angiogenesis from the subchondral bone possibly mediated by vascular endothelial growth factor (VEGF) can be observed in late osteoarthritis samples obtained from patients after total joint replacement. ADAMTS, a disintegrin and metalloproteinase with thrombospondin-1 domains; C/EBP, CCAAT enhancer-binding protein; ESE1, epithelial-specific ETS; ETS, E26 transformation specific; GADD45β, growth arrest and DNA damage 45 beta; HIF-1α, hypoxia-inducible factor-1-alpha; NF-κB, nuclear factor-kappa-B; PA, plasminogen activator; TIMPs, tissue inhibitors of metalloproteinases. ding knockout and transgenic mice [3,4]. The examination of the collagen bundles are thickest and are arranged in a radial cartilage or chondrocytes from patients undergoing joint fashion, and (d) the calcified cartilage zone, located replacement has yielded less information in RA patients, in immediately below the tidemark and above the subchondral which cartilage damage is extensive, than studies of OA bone [5,6]. The calcified zone persists after growth plate patients. In both, the findings do not reflect early disease. closure as the ‘tidemark’ and serves as an important mecha- This review will cover current knowledge about the cellular nical buffer between the uncalcified articular cartilage and the and biochemical mechanisms of cartilage in health and subchondral bone. From the superficial to the deep zone, cell disease derived from studies over the past 10 years. density progressively decreases, whereas cell volume and the proportion of proteoglycan relative to collagen increase. Cartilage in health Cartilage matrix in healthy articular cartilage The interterritorial cartilage matrix, which is composed of a Articular cartilage is composed of four distinct regions: (a) fibrillar collagen network that bestows tensile strength, differs the superficial tangential (or gliding) zone, composed of thin from the territorial matrix closer to the cell, which contains collagen fibrils in tangential array and associated with a high type VI collagen microfibrils but little or no fibrillar collagen. concentration of decorin and a low concentration of aggre- The interterritorial collagen network consists primarily of type can, (b) the middle (or transitional) zone with radial bundles of II collagen fibrils with type XI collagen within the fibril and thicker collagen fibrils, (c) the deep (or radial) zone, in which type IX collagen integrated in the fibril surface with the non- Page 2 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 Figure 2 Cellular interactions in cartilage destruction in rheumatoid arthritis. This scheme represents the progressive destruction of the cartilage associated with the invading synovial pannus in rheumatoid arthritis. As a result of immune cell interactions involving T and B lymphocytes, monocytes/macrophages, and dendritic cells, a number of different cytokines are produced in the synovium due to the influx of inflammatory cells from the circulation and synovial cell hyperplasia. The induction of proinflammatory cytokines produced primarily in the synovium, but also by chondrocytes, results in the upregulation of cartilage-degrading enzymes at the cartilage-pannus junction. Chemokines, nitric oxide (NO), and prostaglandins (PGE ) also contribute to the inflammation and tissue catabolism. ADAMTS, a disintegrin and metalloproteinase with thrombospondin-1 domains; IFN-γ, interferon-gamma; IL, interleukin; MMP, matrix metalloproteinase; SDF-1, stromal derived factor 1; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; Treg, regulatory T (cell). collagen domain projecting outward, permitting association matrilins, and cartilage oligomeric matrix protein (COMP), are with other matrix components and retention of proteoglycans also present in the matrix. COMP acts as a catalyst in [7]. Collagen XXVII, a novel member of the fibrillar collagen collagen fibrillogenesis [9], and interactions between type IX family, also contributes to the formation of a stable cartilage collagen and COMP or matrilin-3 are essential for proper matrix [8]. formation and maintenance of the articular cartilage matrix [10,11]. Perlecan enhances fibril formation [12], and collagen Compressive resistance is bestowed by the large aggre- VI microfibrils connect to collagen II and aggrecan via gating proteoglycan aggrecan, which is attached to complexes of matrilin-1 and biglycan or decorin [13]. hyaluronic acid polymers via link protein. The half-life of aggrecan core protein ranges from 3 to 24 years, and the Chondrocyte physiology and function in healthy glycosaminoglycan components of aggrecan are synthesized articular cartilage more readily under low-turnover conditions, with more rapid Differences in the morphologies of zonal subpopulations of matrix turnover in the pericellular regions. The proteoglycans chondrocytes may reflect matrix composition and are are essential for protecting the collagen network, which has a ascribed largely to differences in the mechanical environment half-life of more than 100 years if not subjected to inappro- [14]. The superficial zone chondrocytes (SZCs) are small and priate degradation. A large number of other noncollagen flattened. The middle zone chondrocytes (MZCs) are rounded, molecules, including biglycan, decorin, fibromodulin, the and the deep zone chondrocytes (DZCs) are grouped in Page 3 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu columns or clusters. In vitro studies with isolated SZCs and connective tissues, a shift in equilibrium between anabolic and DZCs indicate that differences in the expression of mole- catabolic activities occurs in OA as a response to abnormal cules, such as lubricin (also known as superficial zone protein mechanical loading in conjunction with genetic abnormalities or or proteoglycan-4) and PTHrP by SZCs and Indian hedgehog injury to the cartilage and surrounding joint tissues. In RA, the (Ihh) and Runx2 by DZCs, may determine the zonal differ- inflamed synovium is the major source of cytokine-induced ences in matrix composition and function [15-17]. proteinases, although the episodic intra-articular inflammation with synovitis indicates that the synovium may also be a source How chondrocytes maintain their ECM under homeostatic of cytokines and cartilage-degrading proteinases in OA conditions has remained somewhat of a mystery since they [30,31]. However, in OA, these degradative enzymes are do not divide and the matrix isolates them from each other, produced primarily by chondrocytes due to inductive stimuli, but gene expression and protein synthesis may be activated including mechanical stress, injury with attendant by injury. Since the ECM normally shields chondrocytes, they destabilization, oxidative stress, cell-matrix interactions, and lack access to the vascular system and must rely on changes in growth factor responses and matrix during aging. facilitated glucose transport via constitutive glucose trans- porter proteins, GLUT3 and GLUT8 [18], and active Of the proteinases that degrade cartilage collagens and membrane transport systems [19]. Chondrocytes exist at low proteoglycans in joint disease, matrix metalloproteinases oxygen tension within the cartilage matrix, ranging from 10% (MMPs) and aggrecanases have been given the greatest at the surface to less than 1% in the deep zones. In vitro, attention because they degrade native collagens and proteo- chondrocytes adapt to low oxygen tensions by upregulating glycans [32-34]. These include the collagenases (MMP-1, hypoxia-inducible factor-1-alpha (HIF-1α), which can MMP-8, and MMP-13), the gelatinases (MMP-2 and MMP-9), stimulate expression of GLUTs [18], and angiogenic factors stromelysin-1 (MMP-3), and membrane type I (MT1) MMP such as vascular endothelial growth factor (VEGF) [20,21] as (MMP-14) [35]. MMP-10, similar to MMP-3, activates pro- well as a number of genes associated with cartilage anabo- collagenases, is detectable in OA and RA synovial fluids and lism and chondrocyte differentiation [22]. One of our joint tissues, and is produced in vitro by both the synovium laboratories has identified growth arrest and DNA damage 45 and chondrocytes in response to inflammatory cytokines [36]. beta (GADD45β), which previously was implicated as an anti- MMP-14, produced principally by RA synovial tissue, is impor- apoptotic factor during genotoxic stress and cell cycle arrest tant for synovial invasiveness [37], whereas the MMP-14 in other cell types as a survival factor in healthy articular produced by OA chondrocytes activates pro-MMP-13, which chondrocytes [23]. Thus, by modulating the intracellular in turn cleaves pro-MMP-9 [38]. Other MMPs, including expression of survival factors, including HIF-1α and MMP-16 and MMP-28 [32,39], and many members of the GADD45β, chondrocytes survive efficiently in the avascular reprolysin-related proteinases of the ADAM (a disintegrin and cartilage matrix and respond to environmental changes. metalloproteinase) family, including ADAM-17/TACE (tumor necrosis factor-alpha [TNF-α]-converting enzyme), are The aging process may affect the material properties of healthy expressed in cartilage, but their specific roles in cartilage cartilage by altering the content, composition, and structural damage in either OA or RA have yet to be defined [40-42]. organization of collagen and proteoglycan [24-26]. This has Although several of the MMPs, including MMP-3, MMP-8, been attributed to overall decreased anabolism and to the and MMP-14, are capable of degrading proteoglycans, accumulation of advanced glycation end products (AGEs) that ADAMTS (ADAM with thrombospondin-1 domains)-4 and enhance collagen cross-linking [27]. Unless perturbed, healthy ADAMTS-5 are now regarded as the principal aggrecan- chondrocytes remain in a postmitotic quiescent state degrading enzymes in cartilage [43,44]. Aggrecanase inhibi- throughout life, with their decreasing proliferative potential tors that target ADAMTS-5 have been developed and are being attributed to replicative senescence associated with awaiting opportunities for clinical trials in OA [45]. erosion of telomere length [28]. The accumulation of cartilage matrix proteins in the endoplasmic reticulum and Golgi of OA and RA differ with respect to the sites as well as the chondrocytes, which have been modified by oxidative stress origins of disrupted matrix homeostasis. In OA, proteoglycan during aging, may lead to decreased synthesis of cartilage loss and type II collagen cleavage initially occur at the matrix proteins and diminished cell survival [29]. cartilage surface, with evidence of pericellular damage in deeper zones as the lesion progresses [46]. In RA, intrinsic Cartilage in joint disease chondrocyte-derived chondrolytic activity is present at the The loss of balance between cartilage anabolism and cartilage-pannus junction, as well as in deeper zones of catabolism cartilage matrix [47], although elevated levels of MMPs in RA Although the etiologies of OA and RA are different, both synovial fluids likely originate from the synovium. There are diseases present states of inappropriate articular cartilage also differences in matrix synthetic responses in OA and RA. destruction, which is largely the result of elevated expression Whereas type II collagen synthesis is reduced in early RA and activities of proteolytic enzymes. Whereas these enzymes [48], there is evidence of compensatory increases in type II normally are involved in the formation, remodeling, and repair of collagen synthesis in deeper regions of OA cartilage [14]. Page 4 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 This is in agreement with findings of enhanced global syn- has received recent attention with respect to cartilage thesis and gene expression of aggrecan and type II collagen pathology. Human articular chondrocytes can express TLR1, in human OA compared with healthy cartilage [49-51]. TLR2, and TLR4, and the activation of TLR2 by IL-1, TNF-α, Importantly, microarray studies using full-thickness cartilage peptidoglycans, lipopolysaccharide, or fibronectin fragments have also shown that many collagen genes, including increases the production of MMPs, NO, prostaglandin E collagen, type II, alpha 1 (COL2A1), are upregulated in late- (PGE), and VEGF [68-73]. In immune complex-mediated stage OA [23,51]. The latter applies mainly to MZCs and arthritis, TLR4 regulates early-onset inflammation and DZCs, as revealed by laser capture microdissection, whereas cartilage destruction by IL-10-mediated upregulation of Fcγ this anabolic phenotype is less obvious in the degenerated receptor expression and enhanced cytokine production [74]. areas of the upper regions [52]. The IL-18 receptor shares homology with IL-1RI and has a TLR signaling domain. IL-18 has effects similar to IL-1 in Inflammation and cartilage destruction human chondrocytes and stimulates chondrocyte apoptosis, In vivo and in vitro studies have shown that chondrocytes although studies do not suggest a pivotal role in cartilage produce a number of inflammatory mediators, such as inter- destruction in RA [75,76]. IL-33, an ST2-TLR ligand, is leukin-1-beta (IL-1β) and TNF-α, which are present in RA or associated with endothelial cells in RA synovium, but its role OA joint tissues and fluids. Chondrocytes respond to these in cartilage destruction has not been examined [77]. Of proinflammatory cytokines by increasing the production of recent interest are the suppressor of cytokine signaling proteinases, prostaglandins, and nitric oxide (NO) [2,25]. The (SOCS) molecules, including SOCS3, which is induced by first recognition of IL-1 as a regulator of chondrocyte function IL-1 and acts as a negative feedback regulator during insulin- stems largely from work in in vitro culture models showing like growth factor 1 (IGF-1) desensitization in the absence of that activities derived from synovium or monocyte macro- NO by inhibiting insulin receptor substrate 1 (IRS-1) phages induce the production of cartilage-degrading protein- phosphorylation [78]. ases (reviewed in [2,53]). The increased production of prostaglandins by inflammatory IL-1, TNF-α, MMP-1, MMP-3, MMP-8, and MMP-13, and type cytokines is mediated via induction of the expression of not II collagen cleavage epitopes have been shown to colocalize only COX-2 but also microsomal PGE synthase 1 (mPGES-1) in matrix-depleted regions of RA cartilage [48,54] and OA [79,80]. In addition to opposing the induction of COX-2, cartilage [46,55]. In addition, chondrocytes express several inducible nitric oxide synthetase (iNOS), and MMPs and the chemokines as well as chemokine receptors that may suppression of aggrecan synthesis by IL-1, activators of the participate in cartilage catabolism [56,57]. IL-1β also induces peroxisome proliferator-activated receptor gamma (PPARγ), 12,14 other proinflammatory cytokines such as IL-17, which has including the endogenous ligand 15-deoxy-Δ prosta- similar effects on chondrocytes [58,59]. IL-32, a recently glandin J (PGJ ), inhibit IL-1-induced expression of mPGES- 2 2 discovered cytokine that induces TNF-α, IL-1β, IL-6, and 1 [81,82]. Recent evidence indicates that PPARα agonists chemokines, is also expressed in the synovia of RA patients may protect chondrocytes against IL-1-induced responses by and contributes to TNF-α-dependent inflammation and cartilage increasing the expression of IL-1Ra [83]. proteoglycan loss [60]. The importance of synergisms between IL-1 and TNF-α and with other cytokines, such as White adipose tissue has been proposed as a major source IL-17, IL-6, and oncostatin M, in RA or OA joints has been of both pro- and anti-inflammatory cytokines, including IL-1Ra inferred primarily from culture models [61-63]. The up- and IL-10 [84]. Roles for adipokines, identified originally as regulation of cyclooxygenase-2 (COX-2), MMP13, and NOS2 products of adipocytes, have received recent attention, not gene expression by IL-1β in chondrocytes and other cell only because of their relationship to obesity, but also because types is mediated by the induction and activation of a number they can have pro- or anti-inflammatory effects in joint tissues of transcription factors, including nuclear factor-kappa-B and may serve as a link between the neuroendocrine and (NF-κB), CCAAT enhancer-binding protein (C/EBP), activator immune systems [85]. Leptin expression is enhanced during protein 1 (AP-1), and E26 transformation specific family acute inflammation, correlating negatively with inflammatory members, which regulate stress- and inflammation-induced markers in RA sera [86]. The expression of leptin is elevated signaling [64]. IL-1β also uses these mechanisms to in OA cartilage and in osteophytes and it stimulates IGF-1 suppress the expression of a number of genes associated and transforming growth factor-beta-1 (TGF-β1) synthesis in with the differentiated chondrocyte phenotype, including chondrocytes [87]. Leptin synergizes with IL-1 or interferon- COL2A1 and cartilage-derived retinoic acid-sensitive protein/ gamma to increase NO production in chondrocytes [88], and melanoma inhibitory activity (CD-RAP/MIA) [64-66]. The role leptin deficiency attenuates inflammatory processes in experi- of epigenetics in regulating these cellular events in cartilage mental arthritis [89]. It has been proposed that the dys- is under current consideration [67]. regulated balance between leptin and other adipokines, such as adiponectin, promotes destructive inflammatory processes The IL-1R/Toll-like receptor (TLR) superfamily of receptors, [90]. Recent studies indicate that resistin plays a role in early which has a key role in innate immunity and inflammation, stages of trauma-induced OA and in RA at local sites of Page 5 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu inflammation and that serum resistin reflects inflammation and Stress responses in cartilage disease activity [91,92]. Injurious mechanical stress and cartilage matrix degradation products are capable of stimulating the same signaling Effects of mechanical loading pathways as those induced by inflammatory cytokines In young individuals without genetic abnormalities, bio- [98,106-109]. Along with extracellular signal-regulated kinase mechanical factors due to trauma are strongly implicated in 1/2 (ERK1/2), the key protein kinases in the c-jun N-terminal initiating the OA lesion. Mechanical disruption of cell-matrix kinase (JNK), p38 MAPK, and NF-κB signaling cascades are interactions may lead to aberrant chondrocyte behavior, activated, particularly in the upper zones of OA cartilage contributing to fibrillations, cell clusters, and changes in [110]. Furthermore, the engagement of integrin receptors by quantity, distribution, or composition of matrix proteins fibronectin or collagen fragments activates focal adhesion [93,94]. In the early stages of OA, transient increases in kinase signaling and transmits signals intersecting with ERK, chondrocyte proliferation and increased metabolic activity are JNK, and p38 pathways [111,112]. Cascades of multiple associated with a localized loss of proteoglycans at the protein kinases are involved in these responses, including cartilage surface followed by cleavage of type II collagen protein kinase Cζ, which is upregulated in OA cartilage and is (reviewed in [95,96]). These events result in increased water required for activation of NF-κB by IL-1 and TNF-α [113]. content and decreased tensile strength of the matrix as the However, it remains controversial whether inflammatory cyto- lesion progresses. kines are primary or secondary effectors of cartilage damage and defective repair mechanisms in OA since these same Chondrocytes can respond to direct biomechanical pertur- pathways also induce or amplify the expression of cytokine bation by upregulating synthetic activity or by increasing the genes. Interestingly, physiological loading may protect production of inflammatory cytokines, which are also against cartilage loss by inhibiting IκB kinase-beta (IKKβ) produced by other joint tissues. In vitro mechanical loading activity in the canonical NF-κB cascade and attenuating experiments have revealed that injurious static compression NF-κB transcriptional activity [114] as well as by inhibiting stimulates proteoglycan loss, damages the collagen network, TAK1 (TGF-β-activated kinase 1) phosphorylation [115]. In and reduces synthesis of cartilage matrix proteins, whereas addition, genetic factors that cause disruption of chondrocyte dynamic compression increases matrix synthetic activity [97]. differentiation and function and influence the composition and In response to traumatic injury, global gene expression is structure of the cartilage matrix may contribute to abnormal activated, resulting in increased expression of inflammatory biomechanics, independently of the influence of inflammation. mediators, cartilage-degrading proteinases, and stress response factors [98,99]. Neuronal signaling molecules, such Reactive oxygen species (ROS) play a critical role in as substance P and its receptor, NK1, and N-methyl-D- chondrocyte homeostasis, but during aging, trauma, and OA, aspartic acid receptors (NMDARs), which require glutamate partial oxygen variations and mechanical stress as well as and glycine binding for activation, have been implicated in inflammation induce abnormal ROS production, which mechanotransduction in chondrocytes in a recent study [100]. exceeds the antioxidant capacity leading to oxidative stress. ROS and attendant oxidative stress impair growth factor Chondrocytes have receptors for responding to mechanical responses, enhance senescence through telomere shorten- stimulation, many of which are also receptors for ECM ing, and impair mitochondrial function [28,116,117]. ROS components [101]. Among these are several of the integrins levels are also induced by activation of RAGE, the receptor that serve as receptors for fibronectin and type II collagen for AGEs, which regulates chondrocyte and synovial res- fragments, which upon activation stimulate the production of ponses in OA [118]. In chondrocytes, interaction of RAGE proteinases, cytokines, and chemokines [102]. Discoidin with S100A4, a member of the S100 family of calcium- domain receptor 2 (DDR-2), a receptor for native type II binding proteins, stimulates MMP-13 production via phos- collagen fibrils, is activated on chondrocytes via Ras/Raf/Mek phorylation of Pyk2, MAPKs, and NF-κB signaling [119]. signaling and preferentially induces MMP-13 via p38 RAGE expression and S100A1 release are stimulated in mitogen-activated protein kinase (MAPK); this is a universal chondrocytes in vitro and increased in OA cartilage. Trans- mechanism that occurs after loss of proteoglycans, not only glutaminase 1, which is induced by inflammation and stress, in genetic models, but also in surgical mouse OA and human transforms S100A1 into a procatabolic cytokine that signals OA [103]. On the other hand, in RA the cell-cell adhesion through RAGE and the p38 MAPK pathway to induce molecule, cadherin-11, is expressed at the interface between chondrocyte hypertrophy and aggrecan degradation [120]. In the RA synovial pannus and cartilage and facilitates cartilage experimental murine arthritis models, S100A8 and S100A9 invasion and erosion in mouse models in vivo and in human are involved in the upregulation and activation of MMPs and RA tissues in vitro and ex vivo [104] in a TNF-α-dependent aggrecanases [121,122]. In addition, high-mobility group manner [105]. Recent studies indicate that lubricin is an protein 1 (HMGB1), another important RAGE ligand and also important secreted product of chondrocytes, synovial cells, a chromatin architectural protein, is produced by inflamed and other joint tissues which is downregulated in OA and RA synovium and thus acts as a RAGE-dependent proinflam- and modulated by cytokines and growth factors [91,92]. matory cytokine in RA [123]. The differential regulation and Page 6 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 expression of GLUT isoforms by hypoxia, growth factors, and joints. Candidate gene studies and genome-wide linkage inflammatory cytokines may contribute to intracellular stress analyses have revealed polymorphisms or mutations in genes responses [124]. COX-2 is also involved in the chondrocyte encoding ECM and signaling molecules that may determine response to high shear stress, associated with reduced OA susceptibility [136-138]. Gender differences have been antioxidant capacity and increased apoptosis [125]. Modula- noted and gene defects may appear more prominently in tion of such intracellular stress response mechanisms may different joints [136,139]. Gene defects associated with provide strategies for novel therapies. congenital cartilage dysplasias that affect the formation of cartilage matrix and patterning of skeletal elements may Biomarkers of cartilage pathology adversely affect joint alignment and congruity and thus The recent development of assays for specific biological contribute to early onset of OA in these individuals [140]. markers, which reflect quantitative and dynamic changes in Although whole-genome linkage analyses of RA patients have the synthetic and degradation products of cartilage and bone not addressed cartilage specifically, this work has pointed to matrix components, has provided a means of identifying immunological pathways and inflammatory signals that may patients at risk for rapid joint damage and also for early modulate cartilage destruction [141]. monitoring of the efficacy of disease-modifying therapies. Molecules originating from the articular cartilage, including Genomic and proteomic analyses, which have been aggrecan fragments, which contain chondroitin sulfate and performed in cytokine-treated chondrocytes, in cartilage from keratan sulfate, type II collagen fragments, and collagen patients with OA, and in rheumatoid synovium, have provided pyridinoline cross-links, are usually released as degradation some insights into novel mechanisms that might govern products as a result of catabolic processes. Specific chondrocyte responses in both OA and RA [57,63,102,142]. antibodies that detect either synthetic or cleavage epitopes When coupled with biological analyses that address candi- have been developed to study biological markers of cartilage date genes, gene profiling studies of cartilage derived from metabolism in synovial fluids, sera, and urine of patients with OA patients with OA have also begun to yield new information or RA (reviewed in [126-129]). Aggrecan degradation about mediators and pathways [23,51,143,144]. Similarly, products are assayed using antibodies 846, 3B3(-), and 7D4 microarray analysis of cocultures of synovial fibroblasts with that detect chondroitin sulfate neoepitopes, 5D4 that detects chondrocytes in alginate has identified markers of inflam- keratan sulfate epitopes, and the VIDIPEN and NITEGE mation and cartilage destruction associated with RA antibodies that recognize aggrecanase and MMP cleavage pathogenesis [145]. sites, respectively, within the interglobular G1 domain of aggrecan [33]. Similarly, the C2C antibody (previously known Lessons from mouse models as Col2-3/4C ) has been used to detect specific Insight into cartilage pathology in RA has been gleaned from Long mono cleavage of the triple helix of type II collagen [48,129]. the examination of type II collagen-induced arthritis and other Increased ratios of C2C to the synthetic marker, CPII, are types of inflammatory arthritis in mice with transgenic over- associated with a greater likelihood of radiological expression or knockout of genes encoding cytokines, their progression in OA patients [130]. Other markers included receptors, or activators. These studies have led in part to the COMP [131]; YKL-40/HC-gp39, or chitinase 3-like protein 1 conclusion that TNF-α drives acute inflammation whereas (CH3L1), which is induced in chondrocytes by inflammatory IL-1 has a pivotal role in sustaining cartilage erosion [146]. In cytokines [132]; and CD-RAP, also known as MIA [133,134]. support of this concept, crossing arthritic human TNF trans- Such biomarker assays have been used as research tools genic (hTNFtg) mice with IL-1α- and β-deficient strains and are currently under evaluation for monitoring cartilage protected against cartilage erosion without affecting synovial degradation or repair in patient populations. C-reactive inflammation [147]. The success of anti-TNF-α therapy in protein, IL-6, and MMP-3 have also been identified as most but not all patients highlights the importance of potential biomarkers in both RA and OA patient populations. inflammation in joint destruction. A single marker has not proven to be sufficient, however, and the major challenge will be to apply such biomarkers to the In vivo studies have also shown that alterations in cartilage diagnosis and monitoring of disease in individual patients and matrix molecules or in regulators of chondrocyte differen- to correlate them with structural changes in cartilage tiation can lead to OA pathology. The importance of the fine identified by magnetic resonance imaging techniques [135]. protein network and ECM structural integrity in postnatal cartilage health is well documented in studies of deficiencies The genetics of cartilage pathology or mutations in cartilage matrix genes, including Col2a1, Results of epidemiological studies, analysis of patterns of Col9a1, Col11a1, aggrecan, matrilin-3, or fibromodulin alone familial clustering, twin studies, and the characterization of or together with biglycan, which lead to age-dependent rare genetic disorders suggest that genetic abnormalities can cartilage degeneration similar to that in OA patients result in early onset of OA and increased susceptibility to RA. [140,148,149]. Deficiency of Timp3 (tissue inhibitor of metallo- For example, twin studies have shown that the influence of proteinases 3) or postnatal overexpression of constitutively genetic factors may approach 70% in OA that affects certain active Mmp13 also promotes OA-like pathology [150,151]. Page 7 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu Importantly, surgically induced OA disease models in mutant of Mmp13 and Col10a1 in the mouse embryonic growth mice have also implicated ADAMTS5 [152,153], DDR-2 plate [165]. More recently, the findings of our groups suggest [103], and Runx2 [154] as contributors to the onset and/or that GADD45β contributes to the homeostasis of healthy and severity of OA joint disease. Knockout of IL-1β is also early OA articular chondrocytes as an effector of cell survival protective against OA induced by destabilization of the and as one of the factors induced by NF-κB that contributes medial meniscus [155]. Although single gene defects do not to the imbalance in matrix remodelling in OA cartilage by model all aspects of human OA, the loss or mutation of a suppressing COL2A1 gene expression [23] and that the NF- gene that is involved in the synthesis or remodeling of the κB activating kinases, IKKα and IKKβ, differentially contribute cartilage matrix may lead to the disruption of other gene to OA pathology by also regulating matrix remodelling in functions in chondrocytes, thus resulting in joint instability conjunction with chondrocyte differentiation [166]. and OA-like pathology. Thus, novel mechanistic insights into the initiation or progression of OA may be discovered by Endochondral ossification, in which the hypertrophic identifying intracellular effectors of ECM homeostasis and chondrocyte undergoes a stress response associated with remodelling in vitro and evaluating their functions in animal ECM remodelling, has been proposed as a ‘developmental models of OA disease. model’ to understand the contribution of exacerbated environ- mental stresses to OA pathology [167-170]. Changes in the Chondrogenesis, chondrocyte hypertrophy, calcified mineral content and thickness of the calcified cartilage and cartilage,, and bone in cartilage pathology the associated tidemark advancement may be related to During skeletal development, the chondrocytes arise from recapitulation of the hypertrophic phenotype, including mesenchymal progenitors to synthesize the templates, or COL10A1, MMP-13, and Runx2 gene expression, observed cartilage anlagen, for the developing limbs in a process in the deep zone of OA cartilage [167,171]. In addition to known as chondrogenesis [156]. Following mesenchymal COL10A1 and MMP-13, other chondrocyte terminal differen- condensation and chondroprogenitor cell differentiation, tiation-related genes, such as MMP-9 and Ihh, are detected chondrocytes undergo proliferation, terminal differentiation to in the vicinity of early OA lesions along with decreased levels hypertrophy, and apoptosis, whereby hypertrophic cartilage is of Sox9 mRNA [172]. However, Sox9 expression does not replaced by bone in endochondral ossification. A number of always localize with COL2A1 mRNA in adult articular signaling pathways and transcription factors play stage- cartilage [52,173]. Apoptosis is a rare event in OA cartilage specific roles in chondrogenesis and a similar sequence of but may be a consequence of the chondrocyte stress res- events occurs in the postnatal growth plate, leading to rapid ponse associated with hypertrophy [174]. Interestingly, one growth of the skeleton [64,156-158]. of our recent studies indicates that intracellular stress res- ponse genes are upregulated in early OA, whereas a number Chondrogenesis is orchestrated in part by Sox9 and Runx2, of genes encoding cartilage-specific and nonspecific two pivotal transcriptional regulators that determine the fate collagens and other matrix proteins are upregulated in late- of chondrocytes to remain within cartilage or undergo stage OA cartilage [23]. Moreover, articular chondrocytes in hypertrophic maturation prior to ossification and is also micromass culture show ‘phenotypic plasticity’ comparable to subject to complex regulation by interplay of the fibroblast mesenchymal stem cells (MSCs) undergoing chondro- growth factor, TGF-β, BMP, and Wnt signaling pathways genesis, by recapitulating processes akin to chondrocyte [159-162]. Differential signaling during chondrocyte matura- hypertrophy [175], which one of our labs recently has shown tion occurs via TGF-β-regulated signal-transducing mothers to be subject to differential control by canonical NF-κB against decapentaplegic (Smads) 2 and 3 that act to signaling and IKKα [166]. This process may also be maintain articular chondrocytes in an arrested state and modulated by Src kinases [176,177]. BMP-regulated Smads 1 and 5 that accelerate their differen- tiation. Sox9, which is essential for type II collagen (COL2A1) Additional supporting evidence for dysregulation of endo- gene expression, is most highly expressed in proliferating chondral ossification as a factor in OA pathology comes from chondrocytes and has opposing positive and negative effects genetic association studies identifying OA susceptibility on the early and late stages of chondrogenesis, respectively. genes across different populations [138,170,178]. These Sox9 cooperates with two related proteins, L-Sox5 and Sox6, include the genes encoding asporin (ASPN), a TGF-β- which are targets of Sox9 itself and function as architectural binding protein with biglycan and decorin sequence homology HMG-like chromatin modifiers. Moreover, BMP signaling, [179], secreted frizzled-related protein 3 (FRZB), a WNT/β- through the type I Bmpr1a and Bmpr1b receptors, redun- catenin signaling antagonist [180,181], and deiodinase 2 dantly drives chondrogenesis via Sox9, Sox5, and Sox6. In (DIO2), an enzyme that converts inactive thyroid hormone, addition, Runx2, which drives the terminal phase of chondro- T4, to active T3 [182]. The activation of WNT/β-catenin in genesis [163], is subject to direct inhibition by Sox9 [164]. In mature postnatal growth plate chondrocytes stimulates cooperation with BMP-induced Smads, Runx2 also upregu- hypertrophy, matrix mineralization, and expression of VEGF, lates GADD45β, a positive regulator of the terminal hyper- ADAMTS5, MMP-13, and several other MMPs [183]. trophic phase of chondrogenesis which drives the expression Findings from microarray analyses of bone from OA patients Page 8 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 [184] and in Frzb knockout mice [185] also suggest that fat, and muscle cells, are under investigation as sources of signaling modifications in the calcified cartilage could cartilage progenitor cells for cartilage tissue engineering contribute to increased subchondral plate thickness accom- [203-206]. Studies in vitro indicate that the same growth and panying tidemark advancement at the border with the differentiation factors that regulate different stages of articular cartilage and the angiogenesis observed at the cartilage development may be able to promote cartilage osteochondral junction [186]. Moreover, endochondral repair [207-209]. IGF-1 is a potent stimulator of proteoglycan ossification also contributes to the formation of osteophytes synthesis, particularly when combined with other anabolic [187-189]. Interestingly, HMGB1 released by hypertrophic factors, including BMPs [210,211]. Moreover, ex vivo gene cartilage, prior to the onset of programmed cell death, transfer of anabolic factors such as BMPs, TGF-β, and IGF-1 contributes to endochondral ossification by acting as a has been explored as an approach to promote differentiation chemotactic factor for osteoclasts at the growth plate [190], of autologous chondrocytes or MSCs before implantation and HMGB1-induced NF-κB signaling is also required for [212,213]. Recently, endochondral ossification has been cellular chemotaxis in response to HMGB1-RAGE engage- achieved with murine embryonic stem cells in tissue-engi- ment [191]. Thus, IKK-mediated NF-κB signaling not only neered constructs implanted in cranial bone of rats [214]. may intrinsically influence the differentiation of chondrocytes toward a hypertrophy-like state [166], but also could BMP-2 and BMP-7 (osteogenic protein 1) are currently subsequently drive aspects of intercellular communication approved for multiple indications in the area of bone fracture culminating in endochondral ossification [190]. repair and spinal fusion, but the capacity of BMPs and TGF-β to induce chondrocyte hypertrophy in cartilage repair models Changes in the periarticular and subchondral bone also and to promote osteophyte formation may prevent controlled occur in both RA and OA and may contribute to cartilage repair of articular cartilage in vivo [207]. Since the injection of pathology. Receptor activator of NFκB (RANK), a member of free TGF-β or adenovirus-mediated delivery of TGF-β pro- the TNF receptor family, RANK ligand (RANKL), and the motes fibrosis and osteophyte formation, while stimulating soluble receptor osteoprotegerin regulate osteoclast differen- proteoglycan synthesis in cartilage, the local application of tiation and activity and are important mediators of bone molecules that block endogenous TGF-β signaling, such as destruction in RA. IKKβ-mediated, but not IKKα-mediated, the soluble form of TGF-βRII, inhibitory SMADs, or the NF-κB signaling is associated with inflammation-induced physiological antagonist latency-associated peptide 1 (LAP-1), bone loss [192] and is also critical for the survival of osteo- has been proposed as a more effective strategy [188]. clast precursors by suppressing JNK-dependent apoptosis in Additional strategies include gene transfer of Sox9, alone or response to RANKL signaling [193]. IL-17 induces RANKL, together with L-Sox5 and Sox6, into MSCs ex vivo or into inducing bone destruction independently of IL-1 and bypass- joint tissues in vivo to more directly promote the expression ing the requirement for TNF in inflammatory arthritis [58]. of cartilage matrix genes [215,216]. Strategies to stably Although RANK and RANKL are expressed in adult articular express interfering RNAs in vivo could also provide a means chondrocytes, a direct action in cartilage has not been identi- of blocking dysregulated ECM remodelling or inappropriate fied [194]. Since cartilage destruction is not blocked directly endochondral ossification of articular chondrocytes. by the inhibition of RANKL, at least in inflammatory models, indirect effects may occur through protection of the bone Despite intensive investigation of cartilage repair strategies [195,196], as suggested by recent studies in experimental and the increased understanding of the cellular mechanisms models [197,198]. A link between RANKL and WNT has involved, many issues remain to be resolved. These include been suggested by findings in hTNFtg mice and RA tissues, the fabrication and maintenance of the repair tissue in the in which decreased β-catenin and high DKK-1, a WNT same zonal composition as the original cartilage, the recruit- inhibitor, were demonstrated in synovium and in cartilage ment and maintenance of cells with an appropriate chondro- adjacent to inflammatory tissue [199] (reviewed in [200]). In cyte phenotype, and integration of the repair construct with contrast, increased β-catenin was observed in OA cartilage the surrounding cartilage matrix [217]. These issues are also and conditional overexpression in mouse cartilage leads to compounded when cartilage loss is severe or when chronic premature chondrocyte differentiation and development of inflammation exists, as in RA. OA-like phenotype [201]. Interestingly, Runx2-dependent expression of RANKL occurs in hypertrophic chondrocytes at Conclusions the boundary next to the calcifying cartilage in the developing Laboratory investigations in vitro and in vivo regarding the growth plate [202]. role of the chondrocyte in remodeling the cartilage matrix in the RA and OA joint have identified novel molecules and Mesenchymal progenitor cells in cartilage and their use mechanisms and provided new understanding of the contri- in tissue engineering butions of known mediators. In RA, mediators involved in MSCs from bone marrow and other adult tissues, including immunomodulation and synovial cell function, including muscle, adipose tissue, and synovium or other tissue sites, cytokines, chemokines, and adhesion molecules, have primary which have the capacity to differentiate into cartilage, bone, roles in the inflammatory and catabolic processes in the joint, Page 9 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu 6. Goldring MB: Chapter 3: cartilage and chondrocytes. In Kelley’s Textbook of Rheumatology. 8th edition. Edited by Firestein GS, Budd RC, McInnes IB, Sergent JS, Harris ED, Ruddy S. Philadel- The Scientific Basis phia: WB Saunders, an imprint of Elsevier Inc.; 2008:37-69. 7. Eyre DR, Weis MA, Wu JJ: Articular cartilage collagen: an irre- of Rheumatology: placeable framework? Eur Cell Mater 2006, 12:57-63. A Decade of Progress 8. Plumb DA, Dhir V, Mironov A, Ferrara L, Poulsom R, Kadler KE, Thornton DJ, Briggs MD, Boot-Handford RP: Collagen XXVII is developmentally regulated and forms thin fibrillar structures This article is part of a special collection of reviews, The distinct from those of classical vertebrate fibrillar collagens. J Biol Chem 2007, 282:12791-12795. Scientific Basis of Rheumatology: A Decade of 9. Halasz K, Kassner A, Morgelin M, Heinegard D: COMP acts as a Progress, published to mark Arthritis Research & catalyst in collagen fibrillogenesis. J Biol Chem 2007, 282: 31166-31173. Therapy’s 10th anniversary. 10. Leighton MP, Nundlall S, Starborg T, Meadows RS, Suleman F, Knowles L, Wagener R, Thornton DJ, Kadler KE, Boot-Handford Other articles in this series can be found at: RP, Briggs MD: Decreased chondrocyte proliferation and dys- http://arthritis-research.com/sbr regulated apoptosis in the cartilage growth plate are key fea- tures of a murine model of epiphyseal dysplasia caused by a matn3 mutation. Hum Mol Genet 2007, 16:1728-1741. 11. Pirog-Garcia KA, Meadows RS, Knowles L, Heinegard D, Thorn- ton DJ, Kadler KE, Boot-Handford RP, Briggs MD: Reduced cell proliferation and increased apoptosis are significant patho- but they may also, directly or indirectly, promote cartilage logical mechanisms in a murine model of mild pseudoachon- damage. Despite our increasing knowledge of the mecha- droplasia resulting from a mutation in the C-terminal domain nisms regulating the responses of chondrocytes to anabolic of COMP. Hum Mol Genet 2007, 16:2072-2088. 12. Kvist AJ, Johnson AE, Mörgelin M, Gustafsson E, Bengtsson E, and catabolic factors involved in developing and adult Lindblom K, Aszódi A, Fässler R, Sasaki T, Timpl R, Aspberg A: cartilage, the development of disease-modifying therapies for Chondroitin sulfate perlecan enhances collagen fibril forma- OA patients has been elusive. In RA, in which significant tion. Implications for perlecan chondrodysplasias. J Biol Chem 2006, 281:33127-33139. advances have been achieved in our understanding of the 13. Wiberg C, Klatt AR, Wagener R, Paulsson M, Bateman JF, Heine- cellular interactions in the RA joint involving macrophages, T gard D, Morgelin M: Complexes of matrilin-1 and biglycan or decorin connect collagen VI microfibrils to both collagen II and B lymphocytes, and synovial fibroblasts, there is still a and aggrecan. J Biol Chem 2003, 278:37698-37704. need for therapeutic strategies that prevent the extensive 14. Poole AR, Guilak F, Abramson SB: Etiopathogenesis of cartilage and bone loss, despite the clinical success of anti- osteoarthritis. In Osteoarthritis: Diagnosis and Medical/Surgical Management. 4th edition. Edited by Moskowitz RW, Altman RW, TNF therapy for RA. Further work using the principles of cell Hochberg MC, Buckwalter JA, Goldberg VM. Philadelphia: Lippin- and molecular biology, such as those described in this cott, Williams, and Wilkins; 2007:27-49. 15. Cheng C, Conte E, Pleshko-Camacho N, Hidaka C: Differences review, will be necessary for uncovering new therapies for in matrix accumulation and hypertrophy in superficial and targeting cartilage destruction in both degenerative and deep zone chondrocytes are controlled by bone morpho- inflammatory joint disease. genetic protein. Matrix Biol 2007, 26:541-553. 16. Eleswarapu SV, Leipzig ND, Athanasiou KA: Gene expression of single articular chondrocytes. Cell Tissue Res 2007, 327:43- Competing interests The authors declare that they have no competing interests. 17. Chen X, Macica CM, Nasiri A, Broadus AE: Regulation of articu- lar chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Acknowledgments Arthritis Rheum 2008, 58:3788-3797. Research relating to this review was supported by National Institutes of 18. Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland Health (NIH) (Bethesda, MD, USA) grant AG022021 and by the Arthri- JA: Hypoxia inducible factor-1 and facilitative glucose trans- tis Foundation. KBM greatly acknowledges his collaborators in the Lab- porters GLUT1 and GLUT3: putative molecular components of oratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli (Bologna, the oxygen and glucose sensing apparatus in articular chon- Italy), in particular Rosa Maria Borzi, Eleonora Olivotto, Stefania Pagani, drocytes. Histol Histopathol 2005, 20:1327-1338. and Andrea Facchini. The research of KBM was supported in part by 19. Wilkins RJ, Browning JA, Ellory JC: Surviving in a matrix: mem- the Rizzoli Institute, the Carisbo Foundation of Bologna, a Rientro dei brane transport in articular chondrocytes. J Membr Biol 2000, Cervelli award, the MAIN EU FPVI Network of Excellence, and NIH 177:95-108. grant GM066882. 20. Lin C, McGough R, Aswad B, Block JA, Terek R: Hypoxia induces HIF-1a and VEGF expression in chondrosarcoma cells and chondrocytes. J Orthop Res 2004, 22:1175-1181. 21. Pufe T, Lemke A, Kurz B, Petersen W, Tillmann B, Grodzinsky AJ, References 1. Goldring MB, Goldring SR: Osteoarthritis. J Cell Physiol 2007, Mentlein R: Mechanical overload induces VEGF in cartilage discs via hypoxia-inducible factor. Am J Pathol 2004, 164:185- 213:626-634. 2. Dayer JM: The process of identifying and understanding 192. 22. Robins JC, Akeno N, Mukherjee A, Dalal RR, Aronow BJ, cytokines: from basic studies to treating rheumatic diseases. Best Pract Res Clin Rheumatol 2004, 18:31-45. Koopman P, Clemens TL: Hypoxia induces chondrocyte-spe- cific gene expression in mesenchymal cells in association 3. van de Loo FA, Geurts J, van den Berg WB: Gene therapy works in animal models of rheumatoid arthritis...so what! Curr with transcriptional activation of Sox9. Bone 2005, 37:313- Rheumatol Rep 2006, 8:386-393. 4. van den Berg WB: Lessons from animal models of osteoarthri- 23. Ijiri K, Zerbini LF, Peng H, Otu HH, Tsuchimochi K, Otero M, Dragomir C, Walsh N, Bierbaum BE, Mattingly D, van Flandern G, tis. Curr Rheumatol Rep 2008, 10:26-29. 5. Poole AR: Cartilage in health and disease. In Arthritis and Allied Komiya S, Aigner T, Libermann TA, Goldring MB: Differential expression of GADD45b in normal and osteoarthritic carti- Conditions: A Textbook of Rheumatology. 15th edition. Edited by Koopman WS. Philadelphia: Lippincott, Williams, and Wilkins; lage: Potential role in homeostasis of articular chondrocytes. Arthritis Rheum 2008, 58:2075-2087. 2005:223-269. Page 10 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 24. Dudhia J: Aggrecan, aging and assembly in articular cartilage. 45. Gilbert AM, Bursavich MG, Lombardi S, Georgiadis KE, Reifen- Cell Mol Life Sci 2005, 62:2241-2256. berg E, Flannery CR, Morris EA: N-((8-hydroxy-5-substituted- 25. Loeser RF: Molecular mechanisms of cartilage destruction: quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amin o-acetamide mechanics, inflammatory mediators, and aging collide. Arthri- inhibitors of ADAMTS-5 (Aggrecanase-2). Bioorg Med Chem tis Rheum 2006, 54:1357-1360. Lett 2008, 18:6454-6457. 26. Aigner T, Haag J, Martin J, Buckwalter J: Osteoarthritis: aging of 46. Wu W, Billinghurst RC, Pidoux I, Antoniou J, Zukor D, Tanzer M, matrix and cells—going for a remedy. Curr Drug Targets 2007, Poole AR: Sites of collagenase cleavage and denaturation of 8:325-331. type II collagen in aging and osteoarthritic articular cartilage 27. Verzijl N, Bank RA, TeKoppele JM, DeGroot J: AGEing and and their relationship to the distribution of matrix metallopro- osteoarthritis: a different perspective. Curr Opin Rheumatol teinase 1 and matrix metalloproteinase 13. Arthritis Rheum 2003, 15:616-622. 2002, 46:2087-2094. 28. Martin JA, Brown TD, Heiner AD, Buckwalter JA: Chondrocyte 47. Kane D, Jensen LE, Grehan S, Whitehead AS, Bresnihan B, senescence, joint loading and osteoarthritis. Clin Orthop Relat Fitzgerald O: Quantitation of metalloproteinase gene expres- Res 2004, (427 Suppl):S96-103. sion in rheumatoid and psoriatic arthritis synovial tissue distal 29. Yang L, Carlson SG, McBurney D, Horton WE Jr.: Multiple and proximal to the cartilage-pannus junction. J Rheumatol signals induce endoplasmic reticulum stress in both primary 2004, 31:1274-1280. and immortalized chondrocytes resulting in loss of differenti- 48. Fraser A, Fearon U, Billinghurst RC, Ionescu M, Reece R, Barwick ation, impaired cell growth, and apoptosis. J Biol Chem 2005, T, Emery P, Poole AR, Veale DJ: Turnover of type II collagen 280:31156-31165. and aggrecan in cartilage matrix at the onset of inflammatory 30. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan arthritis in humans: relationship to mediators of systemic and B: Synovial tissue inflammation in early and late osteoarthri- local inflammation. Arthritis Rheum 2003, 48:3085-3095. tis. Ann Rheum Dis 2005, 64:1263-1267. 49. Bau B, Gebhard PM, Haag J, Knorr T, Bartnik E, Aigner T: Rela- 31. Pearle AD, Scanzello CR, George S, Mandl LA, DiCarlo EF, Peter- tive messenger RNA expression profiling of collagenases and son M, Sculco TP, Crow MK: Elevated high-sensitivity C-reac- aggrecanases in human articular chondrocytes in vivo and in tive protein levels are associated with local inflammatory vitro. Arthritis Rheum 2002, 46:2648-2657. findings in patients with osteoarthritis. Osteoarthritis Cartilage 50. Hermansson M, Sawaji Y, Bolton M, Alexander S, Wallace A, 2007, 15:516-523. Begum S, Wait R, Saklatvala J: Proteomic analysis of articular 32. Cawston TE, Wilson AJ: Understanding the role of tissue cartilage shows increased type II collagen synthesis in degrading enzymes and their inhibitors in development and osteoarthritis and expression of inhibin bA (activin A), a regu- disease. Best Pract Res Clin Rheumatol 2006, 20:983-1002. latory molecule for chondrocytes. J Biol Chem 2004, 279: 33. Sandy JD: A contentious issue finds some clarity: on the inde- 43514-43521. pendent and complementary roles of aggrecanase activity 51. Aigner T, Fundel K, Saas J, Gebhard PM, Haag J, Weiss T, Zien A, and MMP activity in human joint aggrecanolysis. Osteoarthritis Obermayr F, Zimmer R, Bartnik E: Large-scale gene expression Cartilage 2006, 14:95-100. profiling reveals major pathogenetic pathways of cartilage 34. Rengel Y, Ospelt C, Gay S: Proteinases in the joint: clinical rel- degeneration in osteoarthritis. Arthritis Rheum 2006, 54:3533- evance of proteinases in joint destruction. Arthritis Res Ther 3544. 2007, 9:221. 52. Fukui N, Ikeda Y, Ohnuki T, Tanaka N, Hikita A, Mitomi H, Mori T, 35. Murphy G, Nagase H: Reappraising metalloproteinases in Juji T, Katsuragawa Y, Yamamoto S, Sawabe M, Yamane S, rheumatoid arthritis and osteoarthritis: destruction or repair? Suzuki R, Sandell LJ, Ochi T: Regional differences in chondro- Nat Clin Pract Rheumatol 2008, 4:128-135. cyte metabolism in osteoarthritis: a detailed analysis by laser 36. Barksby HE, Milner JM, Patterson AM, Peake NJ, Hui W, Robson capture microdissection. Arthritis Rheum 2008, 58:154-163. T, Lakey R, Middleton J, Cawston TE, Richards CD, Rowan AD: 53. Arend WP, Goldring MB: The development of anticytokine Matrix metalloproteinase 10 promotion of collagenolysis via therapeutics for rheumatic diseases. Arthritis Rheum 2008, 58: procollagenase activation: implications for cartilage degrada- S102-109. tion in arthritis. Arthritis Rheum 2006, 54:3244-3253. 54. Tetlow LC, Woolley DE: Comparative immunolocalization 37. Rutkauskaite E, Volkmer D, Shigeyama Y, Schedel J, Pap G, studies of collagenase 1 and collagenase 3 production in the Muller-Ladner U, Meinecke I, Alexander D, Gay RE, Drynda S, rheumatoid lesion, and by human chondrocytes and synovio- Neumann W, Michel BA, Aicher WK, Gay S, Pap T: Retroviral cytes in vitro. Br J Rheumatol 1998, 37:64-70. gene transfer of an antisense construct against membrane 55. Tetlow LC, Adlam DJ, Woolley DE: Matrix metalloproteinase type 1 matrix metalloproteinase reduces the invasiveness of and proinflammatory cytokine production by chondrocytes of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2005, human osteoarthritic cartilage. Arthritis Rheum 2001, 44:585- 52:2010-2014. 594. 38. Dreier R, Grassel S, Fuchs S, Schaumburger J, Bruckner P: Pro- 56. Borzi RM, Mazzetti I, Marcu KB, Facchini A: Chemokines in carti- MMP-9 is a specific macrophage product and is activated by lage degradation. Clin Orthop Relat Res 2004, (427 Suppl): osteoarthritic chondrocytes via MMP-3 or a MT1-MMP/MMP- S53-61. 13 cascade. Exp Cell Res 2004, 297:303-312. 57. Sandell LJ, Xing X, Franz C, Davies S, Chang LW, Patra D: Exu- 39. Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter berant expression of chemokine genes by adult human artic- S, Brockbank SM, Edwards DR, Parker AE, Clark IM: Expression ular chondrocytes in response to IL-1b. Osteoarthritis Cartilage profiling of metalloproteinases and their inhibitors in carti- 2008, 16:1560-1571. lage. Arthritis Rheum 2004, 50:131-141. 58. Lubberts E, Koenders MI, van den Berg WB: The role of T cell 40. Burrage PS, Huntington JT, Sporn MB, Brinckerhoff CE: Regula- interleukin-17 in conducting destructive arthritis: lessons tion of matrix metalloproteinase gene expression by a from animal models. Arthritis Res Ther 2005, 7:29-37. retinoid X receptor-specific ligand. Arthritis Rheum 2007, 56: 59. Koenders MI, Joosten LA, van den Berg WB: Potential new 892-904. targets in arthritis therapy: interleukin (IL)-17 and its relation 41. Murphy G, Lee MH: What are the roles of metalloproteinases to tumour necrosis factor and IL-1 in experimental arthritis. in cartilage and bone damage? Ann Rheum Dis 2005, 64 Ann Rheum Dis 2006, 65 Suppl 3:iii29-33. Suppl 4:iv44-47. 60. Joosten LA, Netea MG, Kim SH, Yoon DY, Oppers-Walgreen B, 42. Overall CM, Blobel CP: In search of partners: linking extracel- Radstake TR, Barrera P, van de Loo FA, Dinarello CA, van den lular proteases to substrates. Nat Rev Mol Cell Biol 2007, 8: Berg WB: IL-32, a proinflammatory cytokine in rheumatoid 245-257. arthritis. Proc Natl Acad Sci U S A 2006, 103:3298-3303. 43. Arner EC: Aggrecanase-mediated cartilage degradation. Curr 61. Rowan AD, Koshy PJ, Shingleton WD, Degnan BA, Heath JK, Ver- Opin Pharmacol 2002, 2:322-329. nallis AB, Spaull JR, Life PF, Hudson K, Cawston TE: Synergistic 44. Plaas A, Osborn B, Yoshihara Y, Bai Y, Bloom T, Nelson F, Mikecz effects of glycoprotein 130 binding cytokines in combination K, Sandy JD: Aggrecanolysis in human osteoarthritis: confocal with interleukin-1 on cartilage collagen breakdown. Arthritis localization and biochemical characterization of ADAMTS5- Rheum 2001, 44:1620-1632. hyaluronan complexes in articular cartilages. Osteoarthritis 62. Koshy PJ, Henderson N, Logan C, Life PF, Cawston TE, Rowan Cartilage 2007, 15:719-734. AD: Interleukin 17 induces cartilage collagen breakdown: Page 11 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu novel synergistic effects in combination with proinflammatory synthase 1 in osteoarthritic human cartilage: critical roles of cytokines. Ann Rheum Dis 2002, 61:704-713. the ERK-1/2 and p38 signaling pathways. Arthritis Rheum 63. Barksby HE, Hui W, Wappler I, Peters HH, Milner JM, Richards 2004, 50:2829-2838. CD, Cawston TE, Rowan AD: Interleukin-1 in combination with 80. Whiteman M, Spencer JP, Zhu YZ, Armstrong JS, Schantz JT: oncostatin M up-regulates multiple genes in chondrocytes: Peroxynitrite-modified collagen-II induces p38/ERK and NF- implications for cartilage destruction and repair. Arthritis kB-dependent synthesis of prostaglandin E2 and nitric oxide Rheum 2006, 54:540-550. in chondrogenically differentiated mesenchymal progenitor 64. Goldring MB, Sandell LJ: Transcriptional control of chondrocyte cells. Osteoarthritis Cartilage 2006, 14:460-470. gene expression. In OA, Inflammation and Degradation: A Con- 81. Cheng S, Afif H, Martel-Pelletier J, Pelletier JP, Li X, Farrajota K, tinuum. Edited by Buckwalter J, Lotz M, Stoltz JF. Amsterdam: Lavigne M, Fahmi H: Activation of peroxisome proliferator-acti- IOS Press; 2007:118-142. vated receptor g inhibits interleukin-1b-induced membrane- 65. Imamura T, Imamura C, Iwamoto Y, Sandell LJ: Transcriptional associated prostaglandin E2 synthase-1 expression in human Co-activators CREB-binding protein/p300 increase chondro- synovial fibroblasts by interfering with Egr-1. J Biol Chem cyte Cd-rap gene expression by multiple mechanisms includ- 2004, 279:22057-22065. ing sequestration of the repressor CCAAT/enhancer-binding 82. Li X, Afif H, Cheng S, Martel-Pelletier J, Pelletier JP, Ranger P, protein. J Biol Chem 2005, 280:16625-16634. Fahmi H: Expression and regulation of microsomal 66. Peng H, Tan L, Osaki M, Zhan Y, Ijiri K, Tsuchimochi K, Otero M, prostaglandin E synthase-1 in human osteoarthritic cartilage Wang H, Choy BK, Grall FT, Gu X, Libermann TA, Oettgen P, and chondrocytes. J Rheumatol 2005, 32:887-895. Goldring MB: ESE-1 is a potent repressor of type II collagen 83. Francois M, Richette P, Tsagris L, Fitting C, Lemay C, Benallaoua gene (COL2A1) transcription in human chondrocytes. J Cell M, Tahiri K, Corvol MT: Activation of the peroxisome prolifera- Physiol 2008, 215:562-573. tor-activated receptor a pathway potentiates interleukin-1 67. Roach HI, Yamada N, Cheung KS, Tilley S, Clarke NM, Oreffo receptor antagonist production in cytokine-treated chondro- RO, Kokubun S, Bronner F: Association between the abnormal cytes. Arthritis Rheum 2006, 54:1233-1245. expression of matrix-degrading enzymes by human 84. Dayer JM, Chicheportiche R, Juge-Aubry C, Meier C: Adipose osteoarthritic chondrocytes and demethylation of specific tissue has anti-inflammatory properties: focus on IL-1 recep- CpG sites in the promoter regions. Arthritis Rheum 2005, 52: tor antagonist (IL-1Ra). Ann N Y Acad Sci 2006, 1069:444- 3110-3124. 453. 68. Kim HA, Cho ML, Choi HY, Yoon CS, Jhun JY, Oh HJ, Kim HY: 85. Otero M, Lago R, Gomez R, Dieguez C, Lago F, Gomez-Reino J, The catabolic pathway mediated by Toll-like receptors in Gualillo O: Towards a pro-inflammatory and immunomodula- human osteoarthritic chondrocytes. Arthritis Rheum 2006, 54: tory emerging role of leptin. Rheumatology (Oxford) 2006, 45: 2152-2163. 944-950. 69. Su SL, Tsai CD, Lee CH, Salter DM, Lee HS: Expression and 86. Popa C, Netea MG, Radstake TR, van Riel PL, Barrera P, van der regulation of Toll-like receptor 2 by IL-1b and fibronectin frag- Meer JW: Markers of inflammation are negatively correlated ments in human articular chondrocytes. Osteoarthritis Carti- with serum leptin in rheumatoid arthritis. Ann Rheum Dis lage 2005, 13:879-886. 2005, 64:1195-1198. 70. Varoga D, Paulsen F, Mentlein R, Fay J, Kurz B, Schutz R, Wruck 87. Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, C, Goldring MB, Pufe T: TLR-2-mediated induction of vascular Pottie P: Evidence for a key role of leptin in osteoarthritis. endothelial growth factor (VEGF) in cartilage in septic joint Arthritis Rheum 2003, 48:3118-3129. disease. J Pathol 2006, 210:315-324. 88. Otero M, Lago R, Lago F, Reino JJ, Gualillo O: Signalling 71. Bobacz K, Sunk IG, Hofstaetter JG, Amoyo L, Toma CD, Akira S, pathway involved in nitric oxide synthase type II activation in Weichhart T, Saemann M, Smolen JS: Toll-like receptors and chondrocytes: synergistic effect of leptin with interleukin-1. chondrocytes: the lipopolysaccharide-induced decrease in Arthritis Res Ther 2005, 7:R581-591. cartilage matrix synthesis is dependent on the presence of 89. Palmer G, Aurrand-Lions M, Contassot E, Talabot-Ayer D, toll-like receptor 4 and antagonized by bone morphogenetic Ducrest-Gay D, Vesin C, Chobaz-Peclat V, Busso N, Gabay C: protein 7. Arthritis Rheum 2007, 56:1880-1893. Indirect effects of leptin receptor deficiency on lymphocyte 72. Haglund L, Bernier SM, Onnerfjord P, Recklies AD: Proteomic populations and immune response in db/db mice. J Immunol analysis of the LPS-induced stress response in rat chondro- 2006, 177:2899-2907. cytes reveals induction of innate immune response compo- 90. Lago F, Dieguez C, Gómez-Reino J, Gualillo O: The emerging nents in articular cartilage. Matrix Biol 2008, 27:107-118. role of adipokines as mediators of inflammation and immune 73. Zhang Q, Hui W, Litherland GJ, Barter MJ, Davidson R, Darrah C, responses. Cytokine Growth Factor Rev 2007, 18:313-325. Donell ST, Clark IM, Cawston TE, Robinson JH, Rowan AD, 91. Lee JH, Ort T, Ma K, Picha K, Carton J, Marsters PA, Lohmander Young DA: Differential Toll-like receptor-dependent collage- LS, Baribaud F, Song XY, Blake S: Resistin is elevated follow- nase expression in chondrocytes. Ann Rheum Dis 2008, 67: ing traumatic joint injury and causes matrix degradation and 1633-1641. release of inflammatory cytokines from articular cartilage in 74. van Lent PL, Blom AB, Grevers L, Sloetjes A, van den Berg WB: vitro. Osteoarthritis Cartilage 2008, Nov 1. [Epub ahead of print]. Toll-like receptor 4 induced FcgR expression potentiates early 92. Senolt L, Housa D, Vernerova Z, Jirasek T, Svobodova R, Veigl D, onset of joint inflammation and cartilage destruction during Anderlova K, Muller-Ladner U, Pavelka K, Haluzik M: Resistin in immune complex arthritis: Toll-like receptor 4 largely regu- rheumatoid arthritis synovial tissue, synovial fluid and serum. lates FcgR expression by interleukin 10. Ann Rheum Dis 2007, Ann Rheum Dis 2007, 66:458-463. 66:334-340. 93. Lee JH, Fitzgerald JB, Dimicco MA, Grodzinsky AJ: Mechanical 75. Dai SM, Shan ZZ, Nishioka K, Yudoh K: Implication of inter- injury of cartilage explants causes specific time-dependent leukin 18 in production of matrix metalloproteinases in articu- changes in chondrocyte gene expression. Arthritis Rheum lar chondrocytes in arthritis: direct effect on chondrocytes 2005, 52:2386-2395. may not be pivotal. Ann Rheum Dis 2005, 64:735-742. 94. Alexopoulos LG, Williams GM, Upton ML, Setton LA, Guilak F: 76. John T, Kohl B, Mobasheri A, Ertel W, Shakibaei M: Interleukin- Osteoarthritic changes in the biphasic mechanical properties 18 induces apoptosis in human articular chondrocytes. Histol of the chondrocyte pericellular matrix in articular cartilage. J Histopathol 2007, 22:469-482. Biomech 2005, 38:509-517. 77. Barksby HE, Lea SR, Preshaw PM, Taylor JJ: The expanding 95. Roach HI, Aigner T, Soder S, Haag J, Welkerling H: Pathobiology family of interleukin-1 cytokines and their role in destructive of osteoarthritis: pathomechanisms and potential therapeutic inflammatory disorders. Clin Exp Immunol 2007, 149:217-225. targets. Curr Drug Targets 2007, 8:271-282. 78. Smeets RL, Veenbergen S, Arntz OJ, Bennink MB, Joosten LA, 96. Sandell LJ: Anabolic factors in degenerative joint disease. Curr van den Berg WB, van de Loo FA: A novel role for suppressor Drug Targets 2007, 8:359-365. of cytokine signaling 3 in cartilage destruction via induction of 97. Guilak F, Fermor B, Keefe FJ, Kraus VB, Olson SA, Pisetsky DS, chondrocyte desensitization toward insulin-like growth factor. Setton LA, Weinberg JB: The role of biomechanics and inflam- Arthritis Rheum 2006, 54:1518-1528. mation in cartilage injury and repair. Clin Orthop Relat Res 79. Masuko-Hongo K, Berenbaum F, Humbert L, Salvat C, Goldring 2004, (423):17-26. MB, Thirion S: Up-regulation of microsomal prostaglandin E 98. Fitzgerald JB, Jin M, Dean D, Wood DJ, Zheng MH, Grodzinsky Page 12 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 AJ: Mechanical compression of cartilage explants induces by proteomics: a decrease in mitochondrial superoxide dis- multiple time-dependent gene expression patterns and mutase points to a redox imbalance. Mol Cell Proteomics involves intracellular calcium and cyclic AMP. J Biol Chem 2009, 8:172-189. 2004, 279:19502-19511. 118. Steenvoorden MM, Huizinga TW, Verzijl N, Bank RA, Ronday HK, 99. Kurz B, Lemke AK, Fay J, Pufe T, Grodzinsky AJ, Schunke M: Luning HA, Lafeber FP, Toes RE, DeGroot J: Activation of recep- Pathomechanisms of cartilage destruction by mechanical tor for advanced glycation end products in osteoarthritis injury. Ann Anat 2005, 187:473-485. leads to increased stimulation of chondrocytes and synovio- 100. Ramage L, Martel MA, Hardingham GE, Salter DM: NMDA recep- cytes. Arthritis Rheum 2006, 54:253-263. tor expression and activity in osteoarthritic human articular 119. Yammani RR, Carlson CS, Bresnick AR, Loeser RF: Increase in chondrocytes. Osteoarthritis Cartilage 2008, 16:1576-1584. production of matrix metalloproteinase 13 by human articular 101. Millward-Sadler SJ, Salter DM: Integrin-dependent signal cas- chondrocytes due to stimulation with S100A4: role of the cades in chondrocyte mechanotransduction. Ann Biomed Eng receptor for advanced glycation end products. Arthritis Rheum 2004, 32:435-446. 2006, 54:2901-2911. 102. Pulai JI, Chen H, Im HJ, Kumar S, Hanning C, Hegde PS, Loeser 120. Cecil DL, Terkeltaub R: Transamidation by transglutaminase 2 RF: NF-k B mediates the stimulation of cytokine and transforms S100A11 calgranulin into a procatabolic cytokine chemokine expression by human articular chondrocytes in for chondrocytes. J Immunol 2008, 180:8378-8385. response to fibronectin fragments. J Immunol 2005, 174:5781- 121. van Lent PL, Grevers L, Blom AB, Sloetjes A, Mort JS, Vogl T, 5788. Nacken W, van den Berg WB, Roth J: Myeloid-related proteins 103. Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K, Olsen BR, S100A8/S100A9 regulate joint inflammation and cartilage Goldring MB, Li Y: Increased expression of the collagen recep- destruction during antigen-induced arthritis. Ann Rheum Dis tor discoidin domain receptor 2 in articular cartilage as a key 2008, 67:1750-1758. event in the pathogenesis of osteoarthritis. Arthritis Rheum 122. van Lent PL, Grevers LC, Blom AB, Arntz OJ, van de Loo FA, van 2007, 56:2663-2673. der Kraan P, Abdollahi-Roodsaz S, Srikrishna G, Freeze H, Sloet- 104. Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GF, Chisaka O, jes A, Nacken W, Vogl T, Roth J, van den Berg WB: Stimulation Takeichi M, Brenner MB: Cadherin-11 in synovial lining forma- of chondrocyte-mediated cartilage destruction by S100A8 in tion and pathology in arthritis. Science 2007, 315:1006-1010. experimental murine arthritis. Arthritis Rheum 2008, 58:3776- 105. Vandooren B, Cantaert T, ter Borg M, Noordenbos T, Kuhlman R, 3787. Gerlag D, Bongartz T, Reedquist K, Tak PP, Baeten D: Tumor 123. Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, necrosis factor a drives cadherin 11 expression in rheumatoid Goto M, Inoue K, Yamada S, Ijiri K, Matsunaga S, Nakajima T, inflammation. Arthritis Rheum 2008, 58:3051-3062. Komiya S, Maruyama I: High mobility group box chromosomal 106. Fanning PJ, Emkey G, Smith RJ, Grodzinsky AJ, Szasz N, Trippel protein 1 plays a role in the pathogenesis of rheumatoid SB: Mechanical regulation of mitogen-activated protein arthritis as a novel cytokine. Arthritis Rheum 2003, 48:971-981. kinase signaling in articular cartilage. J Biol Chem 2003, 278: 124. Mobasheri A, Bondy CA, Moley K, Mendes AF, Rosa SC, Richard- 50940-50948. son SM, Hoyland JA, Barrett-Jolley R, Shakibaei M: Facilitative 107. Deschner J, Hofman CR, Piesco NP, Agarwal S: Signal trans- glucose transporters in articular chondrocytes. Expression, duction by mechanical strain in chondrocytes. Curr Opin Clin distribution and functional regulation of GLUT isoforms by Nutr Metab Care 2003, 6:289-293. hypoxia, hypoxia mimetics, growth factors and pro-inflamma- 108. Zhou Y, Millward-Sadler SJ, Lin H, Robinson H, Goldring M, Salter tory cytokines. Adv Anat Embryol Cell Biol 2008, 200:1 p fol- DM, Nuki G: Evidence for JNK-dependent up-regulation of lowing vi, 1-84. proteoglycan synthesis and for activation of JNK1 following 125. Healy ZR, Lee NH, Gao X, Goldring MB, Talalay P, Kensler TW, cyclical mechanical stimulation in a human chondrocyte Konstantopoulos K: Divergent responses of chondrocytes and culture model. Osteoarthritis Cartilage 2007, 15:884-893. endothelial cells to shear stress: cross-talk among COX-2, the 109. Knobloch TJ, Madhavan S, Nam J, Agarwal S Jr., Agarwal S: Reg- phase 2 response, and apoptosis. Proc Natl Acad Sci U S A ulation of chondrocytic gene expression by biomechanical 2005, 102:14010-14015. signals. Crit Rev Eukaryot Gene Expr 2008, 18:139-150. 126.Charni-Ben Tabassi N, Garnero P: Monitoring cartilage 110. Fan Z, Soder S, Oehler S, Fundel K, Aigner T: Activation of inter- turnover. Curr Rheumatol Rep 2007, 9:16-24. leukin-1 signaling cascades in normal and osteoarthritic artic- 127. Rousseau JC, Delmas PD: Biological markers in osteoarthritis. ular cartilage. Am J Pathol 2007, 171:938-946. Nat Clin Pract Rheumatol 2007, 3:346-356. 111.Ronziere MC, Aubert-Foucher E, Gouttenoire J, Bernaud J, 128. Dayer E, Dayer JM, Roux-Lombard P: Primer: the practical use of Herbage D, Mallein-Gerin F: Integrin a1b1 mediates collagen biological markers of rheumatic and systemic inflammatory induction of MMP-13 expression in MC615 chondrocytes. diseases. Nat Clin Pract Rheumatol 2007, 3:512-520. Biochim Biophys Acta 2005, 1746:55-64. 129. Henrotin Y, Addison S, Kraus V, Deberg M: Type II collagen 112. Loeser RF, Forsyth CB, Samarel AM, Im HJ: Fibronectin frag- markers in osteoarthritis: what do they indicate? Curr Opin ment activation of proline-rich tyrosine kinase PYK2 mediates Rheumatol 2007, 19:444-450. integrin signals regulating collagenase-3 expression by 130. Cahue S, Sharma L, Dunlop D, Ionescu M, Song J, Lobanok T, human chondrocytes through a protein kinase C-dependent King L, Poole AR: The ratio of type II collagen breakdown to pathway. J Biol Chem 2003, 278:24577-24585. synthesis and its relationship with the progression of knee 113. LaVallie ER, Chockalingam PS, Collins-Racie LA, Freeman BA, osteoarthritis. Osteoarthritis Cartilage 2007, 15:819-823. Keohan CC, Leitges M, Dorner AJ, Morris EA, Majumdar MK, Arai 131. Lindqvist E, Eberhardt K, Bendtzen K, Heinegard D, Saxne T: M: Protein kinase Cz is up-regulated in osteoarthritic cartilage Prognostic laboratory markers of joint damage in rheumatoid and is required for activation of NF-kB by tumor necrosis arthritis. Ann Rheum Dis 2005, 64:196-201. factor and interleukin-1 in articular chondrocytes. J Biol Chem 132. Baeten D, Steenbakkers PG, Rijnders AM, Boots AM, Veys EM, 2006, 281:24124-24137. De Keyser F: Detection of major histocompatibility complex/ 114. Dossumbekova A, Anghelina M, Madhavan S, He L, Quan N, human cartilage gp-39 complexes in rheumatoid arthritis syn- Knobloch T, Agarwal S: Biomechanical signals inhibit IKK ovitis as a specific and independent histologic marker. Arthri- activity to attenuate NF-kB transcription activity in inflamed tis Rheum 2004, 50:444-451. chondrocytes. Arthritis Rheum 2007, 56:3284-3296. 133. Saito S, Kondo S, Mishima S, Ishiguro N, Hasegawa Y, Sandell 115. Madhavan S, Anghelina M, Sjostrom D, Dossumbekova A, Gut- LJ, Iwata H: Analysis of cartilage-derived retinoic-acid-sensi- tridge DC, Agarwal S: Biomechanical signals suppress TAK1 tive protein (CD-RAP) in synovial fluid from patients with activation to inhibit NF-kB transcriptional activation in fibro- osteoarthritis and rheumatoid arthritis. J Bone Joint Surg Br chondrocytes. J Immunol 2007, 179:6246-6254. 2002, 84:1066-1069. 116. Grishko VI, Ho R, Wilson GL, Pearsall AW 4th: Diminished mito- 134. Vandooren B, Cantaert T, van Lierop MJ, Bos E, De Rycke L, Veys chondrial DNA integrity and repair capacity in OA chondro- EM, De Keyser F, Bresnihan B, Luyten FP, Verdonk PC, Tak PP, cytes. Osteoarthritis Cartilage 2009, 17:107-113. Boots AH, Baeten D: Melanoma inhibitory activity, a biomarker 117.Ruiz-Romero C, Calamia V, Mateos J, Carreira V, Martínez- related to chondrocyte anabolism, is reversibly suppressed by Gomariz M, Fernández M, Blanco FJ: Mitochondrial dysregula- proinflammatory cytokines in rheumatoid arthritis. Ann Rheum tion of osteoarthritic human articular chondrocytes analyzed Dis 2008, Jul 16. [Epub ahead of print]. Page 13 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu 135. Hunter DJ, Li J, LaValley M, Bauer DC, Nevitt M, DeGroot J, Poole Maruyama Z, Komori T, Sato S, Takeda S, Karsenty G, Nakamura R, Eyre D, Guermazi A, Gale D, Felson DT: Cartilage markers K, Chung UI, Kawaguchi H: Contribution of runt-related tran- and their association with cartilage loss on magnetic reso- scription factor 2 to the pathogenesis of osteoarthritis in mice nance imaging in knee osteoarthritis: the Boston Osteoarthri- after induction of knee joint instability. Arthritis Rheum 2006, tis Knee Study. Arthritis Res Ther 2007, 9:R108. 54:2462-2470. 136. Valdes AM, Loughlin J, Oene MV, Chapman K, Surdulescu GL, 155. Glasson SS, Blanchet TJ, Morris EA: The surgical destabiliza- Doherty M, Spector TD: Sex and ethnic differences in the asso- tion of the medial meniscus (DMM) model of osteoarthritis in ciation of ASPN, CALM1, COL2A1, COMP, and FRZB with the 129/SvEv mouse. Osteoarthritis Cartilage 2007, 15:1061- genetic susceptibility to osteoarthritis of the knee. Arthritis 1069. Rheum 2007, 56:137-146. 156. Goldring MB, Tsuchimochi K, Ijiri K: The control of chondrogen- 137. Valdes AM, Van Oene M, Hart DJ, Surdulescu GL, Loughlin J, esis. J Cell Biochem 2006, 97:33-44. Doherty M, Spector TD: Reproducible genetic associations 157. Lefebvre V, Smits P: Transcriptional control of chondrocyte fate between candidate genes and clinical knee osteoarthritis in and differentiation. Birth Defects Res C Embryo Today 2005, men and women. Arthritis Rheum 2006, 54:533-539. 75:200-212. 138. Loughlin J: Polymorphism in signal transduction is a major 158. Hidaka C, Goldring MB: Regulatory mechanisms of chondro- route through which osteoarthritis susceptibility is acting. genesis and implications for understanding articular cartilage Curr Opin Rheumatol 2005, 17:629-633. homeostasis. Curr Rheumatol Rev 2008, 4:136-147. 139. Bukulmez H, Matthews AL, Sullivan CM, Chen C, Kraay MJ, Elston 159. Haque T, Nakada S, Hamdy RC: A review of FGF18: its expres- RC, Moskowitz RW, Goldberg VM, Warman ML: Hip joint sion, signaling pathways and possible functions during replacement surgery for idiopathic osteoarthritis aggregates embryogenesis and post-natal development. Histol in families. Arthritis Res Ther 2006, 8:R25. Histopathol 2007, 22:97-105. 140. Li Y, Xu L, Olsen BR: Lessons from genetic forms of osteo- 160. Wu X, Shi W, Cao X: Multiplicity of BMP signaling in skeletal arthritis for the pathogenesis of the disease. Osteoarthritis development. Ann N Y Acad Sci 2007, 1116:29-49. Cartilage 2007, 15:1101-1105. 161.Yoon BS, Pogue R, Ovchinnikov DA, Yoshii I, Mishina Y, 141. Gregersen PK, Behrens TW: Genetics of autoimmune diseases— Behringer RR, Lyons KM: BMPs regulate multiple aspects of disorders of immune homeostasis. Nat Rev Genet 2006, 7: growth-plate chondrogenesis through opposing actions on 917-928. FGF pathways. Development 2006, 133:4667-4678. 142. Vincenti MP, Brinckerhoff CE: Early response genes induced in 162. Zhong N, Gersch RP, Hadjiargyrou M: Wnt signaling activation chondrocytes stimulated with the inflammatory cytokine inter- during bone regeneration and the role of Dishevelled in chon- leukin-1b. Arthritis Res 2001, 3:381-388. drocyte proliferation and differentiation. Bone 2006, 39:5-16. 143. Attur MG, Dave MN, Akamatsu M, Katoh M, Amin AR: A system 163. Dong YF, Soung do Y, Schwarz EM, O’Keefe RJ, Drissi H: Wnt biology approach to bioinformatics and functional genomics induction of chondrocyte hypertrophy through the Runx2 tran- in complex human diseases: arthritis. Curr Issues Mol Biol scription factor. J Cell Physiol 2006, 208:77-86. 2002, 4:129-146. 164. Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow 144. Sato T, Konomi K, Yamasaki S, Aratani S, Tsuchimochi K, Yok- D, Lee B: Dominance of SOX9 function over RUNX2 during ouchi M, Masuko-Hongo K, Yagishita N, Nakamura H, Komiya S, skeletogenesis. Proc Natl Acad Sci U S A 2006, 103:19004- Beppu M, Aoki H, Nishioka K, Nakajima T: Comparative analysis 19009. of gene expression profiles in intact and damaged regions of 165. Ijiri K, Zerbini LF, Peng H, Correa RG, Lu B, Walsh N, Zhao Y, human osteoarthritic cartilage. Arthritis Rheum 2006, 54:808- Taniguchi N, Huang XL, Otu H, Wang H, Wang JF, Komiya S, 817. Ducy P, Rahman MU, Flavell RA, Gravallese EM, Oettgen P, Liber- 145. Andreas K, Lubke C, Haupl T, Dehne T, Morawietz L, Ringe J, mann TA, Goldring MB: A novel role for GADD45b as a media- Kaps C, Sittinger M: Key regulatory molecules of cartilage tor of MMP-13 gene expression during chondrocyte terminal destruction in rheumatoid arthritis: an in vitro study. Arthritis differentiation. J Biol Chem 2005, 280:38544-38555. Res Ther 2008, 10:R9. 166. Olivotto E, Borzi RM, Vitellozzi R, Pagani S, Facchini A, Battistelli 146. van den Berg WB, van Riel PL: Uncoupling of inflammation and M, Penzo M, Li X, Flamigni F, Li J, Falcieri E, Facchini A, Marcu destruction in rheumatoid arthritis: myth or reality? Arthritis KB: Differential requirements for IKKa and IKKb in the differ- Rheum 2005, 52:995-999. entiation of primary human osteoarthritic chondrocytes. Arthri- 147. Zwerina J, Redlich K, Polzer K, Joosten L, Krönke G, Distler J, tis Rheum 2008, 58:227-239. Hess A, Pundt N, Pap T, Hoffmann O, Gasser J, Scheinecker C, 167. Aigner T, Bartnik E, Sohler F, Zimmer R: Functional genomics of Smolen JS, van den Berg W, Schett G: TNF-induced structural osteoarthritis: on the way to evaluate disease hypotheses. joint damage is mediated by IL-1. Proc Natl Acad Sci U S A Clin Orthop Relat Res 2004, (427 Suppl):S138-143. 2007, 104:11742-11747. 168. Drissi H, Zuscik M, Rosier R, O’Keefe R: Transcriptional regula- 148. Helminen HJ, Saamanen AM, Salminen H, Hyttinen MM: Trans- tion of chondrocyte maturation: potential involvement of tran- genic mouse models for studying the role of cartilage macro- scription factors in OA pathogenesis. Mol Aspects Med 2005, molecules in osteoarthritis. Rheumatology (Oxford) 2002, 41: 26:169-179. 848-856. 169. Terkeltaub RA: Aging, inflammation, and altered chondrocyte 149.Ameye LG, Young MF: Animal models of osteoarthritis: differentiation in articular cartilage calcification and lessons learned while seeking the ‘Holy Grail’. Curr Opin osteoarthritis. Amsterdam: IOS Press; 2007. Rheumatol 2006, 18:537-547. 170. Bos SD, Slagboom PE, Meulenbelt I: New insights into osteo- 150. Sahebjam S, Khokha R, Mort JS: Increased collagen and aggre- arthritis: early developmental features of an ageing-related can degradation with age in the joints of Timp3(-/-) mice. disease. Curr Opin Rheumatol 2008, 20:553-559. Arthritis Rheum 2007, 56:905-909. 171. Wang X, Manner PA, Horner A, Shum L, Tuan RS, Nuckolls GH: 151. Neuhold LA, Killar L, Zhao W, Sung ML, Warner L, Kulik J, Turner Regulation of MMP-13 expression by RUNX2 and FGF2 in J, Wu W, Billinghurst C, Meijers T, Poole AR, Babij P, DeGennaro osteoarthritic cartilage. Osteoarthritis Cartilage 2004, 12:963- LJ: Postnatal expression in hyaline cartilage of constitutively 973. active human collagenase-3 (MMP-13) induces osteoarthritis 172. Tchetina EV, Squires G, Poole AR: Increased type II collagen in mice. J Clin Invest 2001, 107:35-44. degradation and very early focal cartilage degeneration is 152. Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, associated with upregulation of chondrocyte differentiation Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris related genes in early human articular cartilage lesions. J EA: Deletion of active ADAMTS5 prevents cartilage degrada- Rheumatol 2005, 32:876-886. tion in a murine model of osteoarthritis. Nature 2005, 434:644- 173. Aigner T, Gebhard PM, Schmid E, Bau B, Harley V, Poschl E: 648. SOX9 expression does not correlate with type II collagen 153. Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker expression in adult articular chondrocytes. Matrix Biol 2003, CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang 22:363-372. AJ: ADAMTS5 is the major aggrecanase in mouse cartilage in 174. Aigner T, Kim HA, Roach HI: Apoptosis in osteoarthritis. Rheum vivo and in vitro. Nature 2005, 434:648-652. Dis Clin North Am 2004, 30:639-653, xi. 154. Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, 175. Tallheden T, Dennis JE, Lennon DP, Sjogren-Jansson E, Caplan Page 14 of 16 (page number not for citation purposes) Available online http://arthritis-research.com/content/11/3/224 AI, Lindahl A: Phenotypic plasticity of human articular chondro- 194. Komuro H, Olee T, Kuhn K, Quach J, Brinson DC, Shikhman A, cytes. J Bone Joint Surg Am 2003, 85-A Suppl 2:93-100. Valbracht J, Creighton-Achermann L, Lotz M: The osteoprote- 176. Bursell L, Woods A, James CG, Pala D, Leask A, Beier F: Src gerin/receptor activator of nuclear factor kB/receptor activa- kinase inhibition promotes the chondrocyte phenotype. Arthri- tor of nuclear factor kB ligand system in cartilage. Arthritis tis Res Ther 2007, 9:R105. Rheum 2001, 44:2768-2776. 177. Pala D, Kapoor M, Woods A, Kennedy L, Liu S, Chen S, Bursell L, 195. Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y, Lyons KM, Carter DE, Beier F, Leask A: Focal adhesion kinase/ Benoist C, Gravallese EM: TRANCE/RANKL knockout mice are Src suppresses early chondrogenesis: central role of CCN2. J protected from bone erosion in a serum transfer model of Biol Chem 2008, 283:9239-9247. arthritis. Am J Pathol 2001, 159:1689-1699. 178.Valdes AM, Spector TD: The contribution of genes to 196. Schett G, Hayer S, Zwerina J, Redlich K, Smolen JS: Mecha- osteoarthritis. Rheum Dis Clin North Am 2008, 34:581-603. nisms of Disease: the link between RANKL and arthritic bone 179. Kizawa H, Kou I, Iida A, Sudo A, Miyamoto Y, Fukuda A, Mabuchi disease. Nat Clin Pract Rheumatol 2005, 1:47-54. A, Kotani A, Kawakami A, Yamamoto S, Uchida A, Nakamura K, 197. Kadri A, Ea HK, Bazille C, Hannouche D, Liote F, Cohen-Solal ME: Notoya K, Nakamura Y, Ikegawa S: An aspartic acid repeat poly- Osteoprotegerin inhibits cartilage degradation through an morphism in asporin inhibits chondrogenesis and increases effect on trabecular bone in murine experimental osteoarthri- susceptibility to osteoarthritis. Nat Genet 2005, 37:138-144. tis. Arthritis Rheum 2008, 58:2379-2386. 180. Lane NE, Lian K, Nevitt MC, Zmuda JM, Lui L, Li J, Wang J, 198. Kwan Tat S, Pelletier JP, Lajeunesse D, Fahmi H, Lavigne M, Fontecha M, Umblas N, Rosenbach M, de Leon P, Corr M: Friz- Martel-Pelletier J: The differential expression of osteoprote- zled-related protein variants are risk factors for hip gerin (OPG) and receptor activator of nuclear factor kB ligand osteoarthritis. Arthritis Rheum 2006, 54:1246-1254. (RANKL) in human osteoarthritic subchondral bone 181. Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, osteoblasts is an indicator of the metabolic state of these Southam L, Ferreira A, Ciesielski C, Carson DA, Corr M: Func- disease cells. Clin Exp Rheumatol 2008, 26:295-304. tional variants within the secreted frizzled-related protein 3 199. Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, gene are associated with hip osteoarthritis in females. Proc Korb A, Smolen J, Hoffmann M, Scheinecker C, van der Heide D, Natl Acad Sci U S A 2004, 101:9757-9762. Landewe R, Lacey D, Richards WG, Schett G: Dickkopf-1 is a 182. Meulenbelt I, Min JL, Bos S, Riyazi N, Houwing-Duistermaat JJ, master regulator of joint remodeling. Nat Med 2007, 13:156- van der Wijk HJ, Kroon HM, Nakajima M, Ikegawa S, Uitterlinden 163. AG, van Meurs JB, van der Deure WM, Visser TJ, Seymour AB, 200. Goldring SR, Goldring MB: Eating bone or adding it: the Wnt Lakenberg N, van der Breggen R, Kremer D, van Duijn CM, Klop- pathway decides. Nat Med 2007, 13:133-134. penburg M, Loughlin J, Slagboom PE: Identification of DIO2 as a 201. Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, Rosier R, O’Keefe new susceptibility locus for symptomatic osteoarthritis. Hum R, Zuscik M, Chen D: Activation of beta-catenin signaling in Mol Genet 2008, 17:1867-1875. articular chondrocytes leads to osteoarthritis-like phenotype 183. Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, in adult beta-catenin conditional activation mice. J Bone Miner Yamada Y, Costantini F, Wakisaka S, Pacifici M, Iwamoto M, Res 2009, 24:12-21. Enomoto-Iwamoto M: Developmental regulation of Wnt/b- 202. Kishimoto K, Kitazawa R, Kurosaka M, Maeda S, Kitazawa S: catenin signals is required for growth plate assembly, carti- Expression profile of genes related to osteoclastogenesis in lage integrity, and endochondral ossification. J Biol Chem mouse growth plate and articular cartilage. Histochem Cell 2005, 280:19185-19195. Biol 2006, 125:593-602. 184. Hopwood B, Tsykin A, Findlay DM, Fazzalari NL: Microarray gene 203. Barry FP, Murphy JM: Mesenchymal stem cells: clinical applica- expression profiling of osteoarthritic bone suggests altered tions and biological characterization. Int J Biochem Cell Biol bone remodelling, WNT and transforming growth factor-b/ 2004, 36:568-584. bone morphogenic protein signalling. Arthritis Res Ther 2007, 204.Caplan AI: Review: mesenchymal stem cells: cell-based 9:R100. reconstructive therapy in orthopedics. Tissue Eng 2005, 11: 185. Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten 1198-1211. J, Thomas JT, Luyten FP: Articular cartilage and biomechanical 205. Huang JI, Kazmi N, Durbhakula MM, Hering TM, Yoo JU, John- properties of the long bones in Frzb-knockout mice. Arthritis stone B: Chondrogenic potential of progenitor cells derived Rheum 2007, 56:4095-4103. from human bone marrow and adipose tissue: A patient- 186. Walsh DA, Bonnet CS, Turner EL, Wilson D, Situ M, McWilliams matched comparison. J Orthop Res 2005, 23:1383-1389. DF: Angiogenesis in the synovium and at the osteochondral 206. Palmer GD, Steinert A, Pascher A, Gouze E, Gouze JN, Betz O, junction in osteoarthritis. Osteoarthritis Cartilage 2007, 15:743- Johnstone B, Evans CH, Ghivizzani SC: Gene-induced chondro- 751. genesis of primary mesenchymal stem cells in vitro. Mol Ther 187. Burr DB: Anatomy and physiology of the mineralized tissues: 2005, 12:219-228. role in the pathogenesis of osteoarthrosis. Osteoarthritis Carti- 207.Goldring MB: Are bone morphogenetic proteins effective lage 2004, 12 Suppl A:S20-30. inducers of cartilage repair? Ex vivo transduction of muscle- 188. Blaney Davidson EN, van der Kraan PM, van den Berg WB: TGF- derived stem cells. Arthritis Rheum 2006, 54:387-389. b and osteoarthritis. Osteoarthritis Cartilage 2007, 15:597-604. 208. Kuroda R, Usas A, Kubo S, Corsi K, Peng H, Rose T, Cummins J, 189. van der Kraan PM, van den Berg WB: Osteophytes: relevance Fu FH, Huard J: Cartilage repair using bone morphogenetic and biology. Osteoarthritis Cartilage 2007, 15:237-244. protein 4 and muscle-derived stem cells. Arthritis Rheum 190. Taniguchi N, Yoshida K, Ito T, Tsuda M, Mishima Y, Furumatsu T, 2006, 54:433-442. Ronfani L, Abeyama K, Kawahara K, Komiya S, Maruyama I, Lotz 209. Magne D, Vinatier C, Julien M, Weiss P, Guicheux J: Mesenchy- M, Bianchi ME, Asahara H: Stage-specific secretion of HMGB1 mal stem cell therapy to rebuild cartilage. Trends Mol Med in cartilage regulates endochondral ossification. Mol Cell Biol 2005, 11:519-526. 2007, 27:5650-5663. 210. Loeser RF, Chubinskaya S, Pacione C, Im HJ: Basic fibroblast 191. Palumbo R, Galvez BG, Pusterla T, De Marchis F, Cossu G, growth factor inhibits the anabolic activity of insulin-like Marcu KB, Bianchi ME: Cells migrating to sites of tissue growth factor 1 and osteogenic protein 1 in adult human artic- damage in response to the danger signal HMGB1 require NF- ular chondrocytes. Arthritis Rheum 2005, 52:3910-3917. kB activation. J Cell Biol 2007, 179:33-40. 211.Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ: 192. Ruocco MG, Maeda S, Park JM, Lawrence T, Hsu LC, Cao Y, Genetic modification of chondrocytes with insulin-like growth Schett G, Wagner EF, Karin M: I{k}B kinase (IKK){b}, but not factor-1 enhances cartilage healing in an equine model. J IKK{a}, is a critical mediator of osteoclast survival and is Bone Joint Surg Br 2007, 89:672-685. required for inflammation-induced bone loss. J Exp Med 2005, 212. Evans CH: Novel biological approaches to the intra-articular 201:1677-1687. treatment of osteoarthritis. BioDrugs 2005, 19:355-362. 193. Otero JE, Dai S, Foglia D, Alhawagri M, Vacher J, Pasparakis M, 213. Lories RJ, Luyten FP: Bone morphogenetic protein signaling in Abu-Amer Y: Defective osteoclastogenesis by IKKb-null pre- joint homeostasis and disease. Cytokine Growth Factor Rev cursors is a result of receptor activator of NF-kB ligand 2005, 16:287-298. (RANKL)-induced JNK-dependent apoptosis and impaired dif- 214. Jukes JM, Both SK, Leusink A, Sterk LMT, van Blitterswijk CA, de ferentiation. J Biol Chem 2008, 283:24546-24553. Boer J: Endochondral bone tissue engineering using embry- Page 15 of 16 (page number not for citation purposes) Arthritis Research & Therapy Vol 11 No 3 Goldring and Marcu onic stem cells. Proc Natl Acad Sci USA 2008, 105:6840-6845. 215. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S, Takato T, Naka- mura K, Kawaguchi H, Ikegawa S, Chung UI: The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals suffi- cient for induction of permanent cartilage. Arthritis Rheum 2004, 50:3561-3573. 216. Tew SR, Li Y, Pothacharoen P, Tweats LM, Hawkins RE, Harding- ham TE: Retroviral transduction with SOX9 enhances re- expression of the chondrocyte phenotype in passaged osteoarthritic human articular chondrocytes. Osteoarthritis Cartilage 2005, 13:80-89. 217. Kuo CK, Li WJ, Mauck RL, Tuan RS: Cartilage tissue engineer- ing: its potential and uses. Curr Opin Rheumatol 2006, 18:64- Page 16 of 16 (page number not for citation purposes)

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Cartilage homeostasis in health and rheumatic diseases

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