Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cartilage damage in osteoarthritis and rheumatoid arthritis—two unequal siblings

Key Points

  • The molecular mechanisms of cartilage breakdown in rheumatoid arthritis (RA) and osteoarthritis (OA) show considerable overlap, particularly with respect to matrix-degrading enzymes, but also with respect to some inflammatory mediators

  • The loss of phenotypic stability of articular chondrocytes, and initiation of a programme resembling aspects of embryonic endochondral ossification, could explain important features of OA

  • In contrast to OA, RA is associated with a stable, tumour-like activation of fibroblast-like synoviocytes that mediate the destruction of articular cartilage through directed invasion

  • Cartilage has active roles in OA and RA as a signalling scaffold harbouring bioactive matrix components and soluble factors, which interact with embedded chondrocytes and are released upon cartilage degradation

Abstract

Cartilage damage is a key feature of degenerative joint disorders—primarily osteoarthritis (OA)—and chronic inflammatory joint diseases, such as rheumatoid arthritis (RA). Substantial progress has been made towards understanding the mechanisms that lead to degradation of the cartilage matrix in either condition, which ultimately results in the progressive remodelling of affected joints. The available data have shown that the molecular steps in cartilage matrix breakdown overlap in OA and RA. However, they have also, to a great extent, changed our view of the roles of cartilage in the pathogenesis of these disorders. In OA, cartilage loss occurs as part of a complex programme that resembles aspects of embryonic bone formation through endochondral ossification. In RA, early cartilage damage is a key trigger of cellular reactions in the synovium. In a proposed model of RA as a site-specific manifestation of a systemic autoimmune disorder, early cartilage damage in the context of immune activation leads to a specific cellular response within articular joints that could explain not only the organ specificity of RA, but also the chronic nature and perpetuation of the disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Interaction of cartilage matrix and chondrocytes in OA.
Figure 2: Cartilage damage in RA triggers the tissue response and FLS activation.
Figure 3: Comparison of OA and RA.

References

  1. 1

    Pap, T., Korb-Pap, A., Heitzmann, M. & Bertrand, J. in Oxford Textbook of Rheumatology 4th edn Ch. 56 (eds Watts, R. A. et al.) pp. 409–414 (Oxford University Press, 2013).

    Google Scholar 

  2. 2

    Koziel, L., Kunath, M., Kelly, O. G. & Vortkamp, A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev. Cell 6, 801–813 (2004).

    CAS  PubMed  Google Scholar 

  3. 3

    Chuang, C. Y. et al. Heparan sulfate-dependent signaling of fibroblast growth factor 18 by chondrocyte-derived perlecan. Biochemistry 49, 5524–5532 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Sherwood, J. et al. A homeostatic function of CXCR2 signalling in articular cartilage. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2014-205546.

  5. 5

    O'Conor, C. J., Leddy, H. A., Benefield, H. C., Liedtke, W. B. & Guilak, F. TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc. Natl Acad. Sci. USA 111, 1316–1321 (2014).

    CAS  PubMed  Google Scholar 

  6. 6

    DeLise, A. M., Fischer, L. & Tuan, R. S. Cellular interactions and signaling in cartilage development. Osteoarthritis Cartilage 8, 309–334 (2000).

    CAS  Google Scholar 

  7. 7

    Kerkhof, H. J. et al. Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium. Osteoarthritis Cartilage 19, 254–264 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Goldring, M. B. & Goldring, S. R. Osteoarthritis. J. Cell. Physiol. 213, 626–634 (2007).

    CAS  PubMed  Google Scholar 

  9. 9

    Conaghan, P. G. Osteoarthritis in 2012: parallel evolution of OA phenotypes and therapies. Nat. Rev. Rheumatol. 9, 68–70 (2013).

    Google Scholar 

  10. 10

    Wang, M. et al. Recent progress in understanding molecular mechanisms of cartilage degeneration during osteoarthritis. Ann. NY Acad. Sci. 1240, 61–69 (2011).

    CAS  Google Scholar 

  11. 11

    Felson, D. T. Osteoarthritis as a disease of mechanics. Osteoarthritis Cartilage 21, 10–15 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Wluka, A. E., Lombard, C. B. & Cicuttini, F. M. Tackling obesity in knee osteoarthritis. Nat. Rev. Rheumatol. 9, 225–235 (2013).

    PubMed  Google Scholar 

  13. 13

    Meulenbelt, I., Kraus, V. B., Sandell, L. J. & Loughlin, J. Summary of the OA biomarkers workshop 2010 - genetics and genomics: new targets in OA. Osteoarthritis Cartilage 19, 1091–1094 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Zhai, G. et al. A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-OA consortium. J. Med. Genet. 46, 614–616 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Troeberg, L. & Nagase, H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim. Biophys. Acta 1824, 133–145 (2012).

    CAS  Google Scholar 

  16. 16

    Smith, G. N. Jr. The role of collagenolytic matrix metalloproteinases in the loss of articular cartilage in osteoarthritis. Front. Biosci. 11, 3081–3095 (2006).

    CAS  Google Scholar 

  17. 17

    Verma, P. & Dalal, K. ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J. Cell. Biochem. 112, 3507–3514 (2011).

    CAS  Google Scholar 

  18. 18

    De Croos, J. N. et al. Membrane type-1 matrix metalloproteinase is induced following cyclic compression of in vitro grown bovine chondrocytes. Osteoarthritis Cartilage 15, 1301–1310 (2007).

    CAS  Google Scholar 

  19. 19

    Honsawek, S. et al. Association of MMP-3 (-1612 5A/6A) polymorphism with knee osteoarthritis in Thai population. Rheumatol. Int. 33, 435–439 (2013).

    CAS  Google Scholar 

  20. 20

    Lin, P. M., Chen, C. T. & Torzilli, P. A. Increased stromelysin-1 (MMP-3), proteoglycan degradation (3B3- and 7D4) and collagen damage in cyclically load-injured articular cartilage. Osteoarthritis Cartilage 12, 485–496 (2004).

    Google Scholar 

  21. 21

    Huebner, J. L., Otterness, I. G., Freund, E. M., Caterson, B. & Kraus, V. B. Collagenase 1 and collagenase 3 expression in a guinea pig model of osteoarthritis. Arthritis Rheum. 41, 877–890 (1998).

    CAS  Google Scholar 

  22. 22

    Yoshihara, Y. et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann. Rheum. Dis. 59, 455–461 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Lim, N. H., Meinjohanns, E., Meldal, M., Bou-Gharios, G. & Nagase, H. In vivo imaging of MMP-13 activity in the murine destabilised medial meniscus surgical model of osteoarthritis. Osteoarthritis Cartilage 22, 862–868 (2014).

    CAS  Google Scholar 

  24. 24

    Tetlow, L. C., Adlam, D. J. & Woolley, D. E. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum. 44, 585–594 (2001).

    CAS  Google Scholar 

  25. 25

    Hirata, M. et al. C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes. Hum. Mol. Genet. 21, 1111–1123 (2012).

    CAS  Google Scholar 

  26. 26

    Burrage, P. S., Mix, K. S. & Brinckerhoff, C. E. Matrix metalloproteinases: role in arthritis. Front. Biosci. 11, 529–543 (2006).

    CAS  Google Scholar 

  27. 27

    Borden, P. et al. Cytokine control of interstitial collagenase and collagenase-3 gene expression in human chondrocytes. J. Biol. Chem. 271, 23577–23581 (1996).

    CAS  Google Scholar 

  28. 28

    Fan, Z., Yang, H., Bau, B., Söder, S. & Aigner, T. Role of mitogen-activated protein kinases and NFκB on IL-1β-induced effects on collagen type II, MMP-1 and 13 mRNA expression in normal articular human chondrocytes. Rheumatol. Int. 26, 900–903 (2006).

    CAS  Google Scholar 

  29. 29

    Neuhold, L. A. et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J. Clin. Invest. 107, 35–44 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Little, C. B. et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 60, 3723–3733 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Stanton, H. et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434, 648–652 (2005).

    CAS  Google Scholar 

  32. 32

    Song, R. H. et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum. 56, 575–85 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Majumdar, M. K. et al. Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis. Arthritis Rheum. 56, 3670–3674 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Yamanishi, Y. et al. Expression and regulation of aggrecanase in arthritis: the role of TGF-β. J. Immunol. 168, 1405–1412 (2002).

    CAS  Google Scholar 

  35. 35

    Wylie, J. D., Ho, J. C., Singh, S., McCulloch, D. R. & Apte, S. S. Adamts5 (aggrecanase-2) is widely expressed in the mouse musculoskeletal system and is induced in specific regions of knee joint explants by inflammatory cytokines. J. Orthop. Res. 30, 226–233 (2012).

    CAS  Google Scholar 

  36. 36

    Echtermeyer, F. et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat. Med. 15, 1072–1076 (2009).

    CAS  PubMed  Google Scholar 

  37. 37

    Wang, J. et al. TNF-α and IL-1β promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. J. Biol. Chem. 286, 39738–39749 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Brew, C. J., Clegg, P. D., Boot-Handford, R. P., Andrew, J. G. & Hardingham, T. Gene expression in human chondrocytes in late osteoarthritis is changed in both fibrillated and intact cartilage without evidence of generalised chondrocyte hypertrophy. Ann. Rheum. Dis. 69, 234–240 (2010).

    CAS  Google Scholar 

  39. 39

    Dy, P. et al. Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev. Cell 22, 597–609 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Leung, V. Y. et al. SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet. 7, e1002356 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Yagi, R., McBurney, D., Laverty, D., Weiner, S. & Horton, W. E. Jr. Intrajoint comparisons of gene expression patterns in human osteoarthritis suggest a change in chondrocyte phenotype. J. Orthop. Res. 23, 1128–1138 (2005).

    CAS  Google Scholar 

  42. 42

    Haag, J., Gebhard, P. M. & Aigner, T. SOX gene expression in human osteoarthritic cartilage. Pathobiology 75, 195–199 (2008).

    CAS  Google Scholar 

  43. 43

    Salminen, H., Vuorio, E. & Säämänen, A. M. Expression of Sox9 and type IIA procollagen during attempted repair of articular cartilage damage in a transgenic mouse model of osteoarthritis. Arthritis Rheum. 44, 947–955 (2001).

    CAS  Google Scholar 

  44. 44

    Henry, S. P., Liang, S., Akdemir, K. C. & de Crombrugghe, B. The postnatal role of Sox9 in cartilage. J. Bone Miner. Res. 27, 2511–2525 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Tew, S. R. et al. Retroviral transduction with SOX9 enhances re-expression of the chondrocyte phenotype in passaged osteoarthritic human articular chondrocytes. Osteoarthritis Cartilage 13, 80–89 (2005).

    Google Scholar 

  46. 46

    Cucchiarini, M. et al. Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9. Arthritis Rheum. 56, 158–167 (2007).

    CAS  Google Scholar 

  47. 47

    Pullig, O., Weseloh, G., Klatt, A. R., Wagener, R. & Swoboda, B. Matrilin-3 in human articular cartilage: increased expression in osteoarthritis. Osteoarthritis Cartilage 10, 253–263 (2002).

    CAS  Google Scholar 

  48. 48

    Stefánsson, S. E. et al. Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am. J. Hum. Genet. 72, 1448–1459 (2003).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Eliasson, G. J., Verbruggen, G., Stefansson, S. E., Ingvarsson, T. & Jonsson, H. Hand radiology characteristics of patients carrying the T(303)M mutation in the gene for matrilin-3. Scand. J. Rheumatol. 35, 138–142 (2006).

    CAS  Google Scholar 

  50. 50

    Vincourt, J. B. et al. Increased expression of matrilin-3 not only in osteoarthritic articular cartilage but also in cartilage-forming tumors, and down-regulation of SOX9 via epidermal growth factor domain 1-dependent signaling. Arthritis Rheum. 58, 2798–2808 (2008).

    Google Scholar 

  51. 51

    Chintala, S. K., Miller, R. R. & McDevitt, C. A. Basic fibroblast growth factor binds to heparan sulfate in the extracellular matrix of rat growth plate chondrocytes. Arch. Biochem. Biophys. 310, 180–186 (1994).

    CAS  Google Scholar 

  52. 52

    Vincent, T. L., McLean, C. J., Full, L. E., Peston, D. & Saklatvala, J. FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer. Osteoarthritis Cartilage 15, 752–763 (2007).

    CAS  Google Scholar 

  53. 53

    Chia, S. L. et al. Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheum. 60, 2019–2027 (2009).

    CAS  Google Scholar 

  54. 54

    Kawaguchi, H. Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models. Mol. Cells 25, 1–6 (2008).

    CAS  Google Scholar 

  55. 55

    Dreier, R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res. Ther. 12, 216 (2010).

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Karlsson, C., Brantsing, C., Egell, S. & Lindahl, A. Notch1, Jagged1, and HES5 are abundantly expressed in osteoarthritis. Cells Tissues Organs 188, 287–298 (2008).

    CAS  Google Scholar 

  57. 57

    Hosaka, Y. et al. Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc. Natl Acad. Sci. USA 110, 1875–1880 (2013).

    CAS  Google Scholar 

  58. 58

    Lingaraj, K., Poh, C. K. & Wang, W. Vascular endothelial growth factor (VEGF) is expressed during articular cartilage growth and re-expressed in osteoarthritis. Ann. Acad. Med. Singapore 39, 399–403 (2010).

    Google Scholar 

  59. 59

    Mitchell, P. G. et al. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J. Clin. Invest. 97, 761–768 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Mirando, A. J. et al. RBP-Jκ-dependent Notch signaling is required for murine articular cartilage and joint maintenance. Arthritis Rheum. 65, 2623–2633 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Bertrand, J. et al. Syndecan 4 supports bone fracture repair, but not fetal skeletal development, in mice. Arthritis Rheum. 65, 743–752 (2013).

    CAS  Google Scholar 

  62. 62

    Ko, Y. et al. Matrilin-3 is dispensable for mouse skeletal growth and development. Mol. Cell Biol. 24, 1691–1699 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Saito, T. et al. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nat. Med. 16, 678–686 (2010).

    CAS  PubMed  Google Scholar 

  64. 64

    Araldi, E., Khatri, R., Giaccia, A. J., Simon, M. C. & Schipani, E. Lack of HIF-2α in limb bud mesenchyme causes a modest and transient delay of endochondral bone development. Nat. Med. 17, 25–26 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Nakajima, M. et al. Replication studies in various ethnic populations do not support the association of the HIF-2α SNP rs17039192 with knee osteoarthritis. Nat. Med. 17, 26–27 (2011).

    CAS  Google Scholar 

  66. 66

    Kamekura, S. et al. Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum. 54, 2462–2470 (2006).

    CAS  Google Scholar 

  67. 67

    Lin, A. C. et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat. Med. 15, 1421–1425 (2009).

    CAS  PubMed  Google Scholar 

  68. 68

    Goldring, M. B. & Otero, M. Inflammation in osteoarthritis. Curr. Opin. Rheumatol. 23, 471–478 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 1674–1679 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Edd, S. N., Giori, N. J. & Andriacchi, T. P. The role of inflammation in the initiation of osteoarthritis after meniscal damage. J. Biomech. 48, 1420–1426 (2015).

    Google Scholar 

  71. 71

    Gierman, L. M. et al. Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis Rheum. 64, 1172–1181 (2012).

    CAS  Google Scholar 

  72. 72

    Griffin, T. M., Huebner, J. L., Kraus, V. B., Yan, Z. & Guilak, F. Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: effects of short-term exercise. Arthritis Rheum. 64, 443–453 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Ashraf, S., Mapp, P. I. & Walsh, D. A. Contributions of angiogenesis to inflammation, joint damage, and pain in a rat model of osteoarthritis. Arthritis Rheum. 63, 2700–2710 (2011).

    CAS  Google Scholar 

  74. 74

    Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16–21 (2013).

    CAS  PubMed  Google Scholar 

  75. 75

    Bougault, C. et al. Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models. Arthritis Rheum. 64, 3972–3981 (2012).

    CAS  PubMed  Google Scholar 

  76. 76

    de Hooge, A. S. et al. Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging. Osteoarthritis Cartilage 13, 66–73 (2005).

    Google Scholar 

  77. 77

    Kim, H. A. et al. The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes. Arthritis Rheum. 54, 2152–2163 (2006).

    CAS  Google Scholar 

  78. 78

    Liu-Bryan, R. & Terkeltaub, R. Chondrocyte innate immune myeloid differentiation factor 88-dependent signaling drives procatabolic effects of the endogenous Toll-like receptor 2/Toll-like receptor 4 ligands low molecular weight hyaluronan and high mobility group box chromosomal protein 1 in mice. Arthritis Rheum. 62, 2004–2012 (2010).

    PubMed  PubMed Central  Google Scholar 

  79. 79

    Gondokaryono, S. P. et al. The extra domain A of fibronectin stimulates murine mast cells via toll-like receptor 4. J. Leukoc. Biol. 82, 657–665 (2007).

    CAS  PubMed  Google Scholar 

  80. 80

    Lefebvre, J. S. et al. Extra domain A of fibronectin primes leukotriene biosynthesis and stimulates neutrophil migration through activation of Toll-like receptor 4. Arthritis Rheum. 63, 1527–1533 (2011).

    CAS  Google Scholar 

  81. 81

    Midwood, K. et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 15, 774–780 (2009).

    CAS  PubMed  Google Scholar 

  82. 82

    Schaefer, L. et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J. Clin. Invest. 115, 2223–2233 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Rushton, M. D. et al. Characterization of the cartilage DNA methylome in knee and hip osteoarthritis. Arthritis Rheumatol. 66, 2450–2460 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Moazedi-Fuerst, F. C. et al. Epigenetic differences in human cartilage between mild and severe OA. J. Orthop. Res. 32, 1636–1645 (2014).

    CAS  Google Scholar 

  85. 85

    Kim, K. I., Park, Y. S. & Im, G. I. Changes in the epigenetic status of the SOX-9 promoter in human osteoarthritic cartilage. J. Bone Miner. Res. 28, 1050–1060 (2013).

    CAS  Google Scholar 

  86. 86

    Imagawa, K. et al. Association of reduced type IX collagen gene expression in human osteoarthritic chondrocytes with epigenetic silencing by DNA hypermethylation. Arthritis Rheumatol. 66, 3040–3051 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Muller-Ladner, U., Pap, T., Gay, R. E., Neidhart, M. & Gay, S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 1, 102–110 (2005).

    PubMed  Google Scholar 

  88. 88

    Rommel, C., Camps, M. & Ji, H. PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat. Rev. Immunol. 7, 191–201 (2007).

    CAS  Google Scholar 

  89. 89

    Brennan, F. M. & McInnes, I. B. Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest. 118, 3537–3545 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Klareskog, L., Padyukov, L., Lorentzen, J. & Alfredsson, L. Mechanisms of disease: genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 2, 425–433 (2006).

    CAS  Google Scholar 

  91. 91

    Kobezda, T., Ghassemi-Nejad, S., Mikecz, K., Glant, T. T. & Szekanecz, Z. Of mice and men: how animal models advance our understanding of T-cell function in RA. Nat. Rev. Rheumatol. 10, 160–170 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Huber, L. C. et al. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford) 45, 669–675 (2006).

    CAS  Google Scholar 

  93. 93

    Niedermeier, M., Pap, T. & Korb, A. Therapeutic opportunities in fibroblasts in inflammatory arthritis. Best Pract. Res. Clin. Rheumatol. 24, 527–540 (2010).

    Google Scholar 

  94. 94

    Bottini, N. & Firestein, G. S. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol. 9, 24–33 (2013).

    CAS  Google Scholar 

  95. 95

    Pap, T. et al. Expression of membrane-type matrix metallo proteinases (MT-MMP), MMP-2 and MMP-13 in the rheumatoid arthritis (RA) synovium [abstract 106]. Arthritis Rheum. 42, S88 (1999).

    Google Scholar 

  96. 96

    Rutkauskaite, E. et al. Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 52, 2010–2014 (2005).

    CAS  Google Scholar 

  97. 97

    Miller, M. C. et al. Membrane type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritis. Arthritis Rheum. 60, 686–697 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Pap, T., Müller-Ladner, U., Gay, R. E. & Gay, S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2, 361–367 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Rinaldi, N. et al. Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Ann. Rheum. Dis. 56, 45–51 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Lowin, T. & Straub, R. H. Integrins and their ligands in rheumatoid arthritis. Arthritis Res. Ther. 13, 244 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Patterson, A. M. et al. Differential expression of syndecans and glypicans in chronically inflamed synovium. Ann. Rheum. Dis. 67, 592–601 (2008).

    CAS  Google Scholar 

  102. 102

    Kehoe, O. et al. Syndecan-3 is selectively pro-inflammatory in the joint and contributes to antigen-induced arthritis in mice. Arthritis Res. Ther. 16, R148 (2014).

    PubMed  PubMed Central  Google Scholar 

  103. 103

    Korb-Pap, A. et al. Early structural changes in cartilage and bone are required for the attachment and invasion of inflamed synovial tissue during destructive inflammatory arthritis. Ann. Rheum. Dis. 71, 1004–1011 (2012).

    CAS  Google Scholar 

  104. 104

    Peters, M. A. et al. The loss of α2β1 integrin suppresses joint inflammation and cartilage destruction in mouse models of rheumatoid arthritis. Arthritis Rheum. 64, 1359–1368 (2012).

    CAS  Google Scholar 

  105. 105

    Zwerina, J. et al. TNF-induced structural joint damage is mediated by IL-1. Proc. Natl Acad. Sci. USA 104, 11742–11747 (2007).

    CAS  PubMed  Google Scholar 

  106. 106

    Shiozawa, S. et al. Pathogenic importance of fibronectin in the superficial region of articular cartilage as a local factor for the induction of pannus extension on rheumatoid articular cartilage. Ann. Rheum. Dis. 51, 869–873 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Yasuda, T. Cartilage destruction by matrix degradation products. Mod. Rheumatol. 16, 197–205 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Shelef, M. A., Bennin, D. A., Mosher, D. F. & Huttenlocher, A. Citrullination of fibronectin modulates synovial fibroblast behavior. Arthritis Res. Ther. 14, R240 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Sipilä, K. et al. Citrullination of collagen II affects integrin-mediated cell adhesion in a receptor-specific manner. FASEB J. 28, 3758–3768 (2014).

    Google Scholar 

  110. 110

    Podolin, P. L. et al. A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J. Immunol. 169, 6435–6444 (2002).

    CAS  Google Scholar 

  111. 111

    Grespan, R. et al. CXCR2-specific chemokines mediate leukotriene B4-dependent recruitment of neutrophils to inflamed joints in mice with antigen-induced arthritis. Arthritis Rheum. 58, 2030–2040 (2008).

    CAS  PubMed  Google Scholar 

  112. 112

    Manabe, N. et al. Involvement of fibroblast growth factor-2 in joint destruction of rheumatoid arthritis patients. Rheumatology (Oxford) 38, 714–720 (1999).

    CAS  Google Scholar 

  113. 113

    Yamashita, A. et al. Fibroblast growth factor-2 determines severity of joint disease in adjuvant-induced arthritis in rats. J. Immunol. 168, 450–457 (2002).

    CAS  Google Scholar 

  114. 114

    Nakano, K., Okada, Y., Saito, K. & Tanaka, Y. Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblasts. Arthritis Rheum. 50, 2450–2458 (2004).

    CAS  Google Scholar 

  115. 115

    Abe, K., Aslam, A., Walls, A. F., Sato, T. & Inoue, H. Up-regulation of protease-activated receptor-2 by bFGF in cultured human synovial fibroblasts. Life Sci. 79, 898–904 (2006).

    CAS  Google Scholar 

  116. 116

    Raza, K. et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res. Ther. 7, R784–R795 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Pap, T. & Gay, S. in Kelley's Textbook of Rheumatology 8th edn (eds Firestein, G. S. et al.) 201–214 (Saunders Elsevier, 2009).

    Google Scholar 

  118. 118

    Karouzakis, E., Gay, R. E., Michel, B. A., Gay, S. & Neidhart, M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 60, 3613–3622 (2009).

    CAS  Google Scholar 

  119. 119

    Nakano, K., Whitaker, J. W., Boyle, D. L., Wang, W. & Firestein, G. S. DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. 72, 110–117 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Wada, T. T. et al. Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts. Biochem. Biophys. Res. Commun. 444, 682–686 (2014).

    CAS  Google Scholar 

  121. 121

    Karouzakis, E. et al. Epigenome analysis reveals TBX5 as a novel transcription factor involved in the activation of rheumatoid arthritis synovial fibroblasts. J. Immunol. 193, 4945–4951 (2014).

    CAS  Google Scholar 

  122. 122

    Frank, S. et al. Regulation of matrixmetalloproteinase-3 and matrixmetalloproteinase-13 by SUMO-2/3 through the transcription factor NF-κB. Ann. Rheum. Dis. 72, 1874–1881 (2013).

    CAS  Google Scholar 

  123. 123

    Li, F. et al. SUMO-conjugating enzyme UBC9 promotes proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis. Inflammation 37, 1134–1141 (2014).

    CAS  Google Scholar 

  124. 124

    Maciejewska-Rodrigues, H. et al. Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression. J. Autoimmun. 35, 15–22 (2010).

    CAS  Google Scholar 

  125. 125

    Meinecke, I. et al. Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc. Natl Acad. Sci. USA 104, 5073–5078 (2007).

    CAS  Google Scholar 

  126. 126

    Kato, M., Ospelt, C., Gay, R. E., Gay, S. & Klein, K. Dual role of autophagy in stress-induced cell death in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol. 66, 40–48 (2014).

    CAS  Google Scholar 

  127. 127

    Nakano, K., Boyle, D. L. & Firestein, G. S. Regulation of DNA methylation in rheumatoid arthritis synoviocytes. J. Immunol. 190, 1297–1303 (2013).

    CAS  Google Scholar 

  128. 128

    Angiolilli, C. et al. Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2014-205635.

  129. 129

    Patel, R., Filer, A., Barone, F. & Buckley, C. D. Stroma: fertile soil for inflammation. Best Pract. Res. Clin. Rheumatol. 28, 565–576 (2014).

    Google Scholar 

  130. 130

    Lefèvre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009).

    PubMed  PubMed Central  Google Scholar 

  131. 131

    Krzeski, P. et al. Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study. Arthritis Res. Ther. 9, R109 (2007).

    PubMed  PubMed Central  Google Scholar 

  132. 132

    Doherty, M. & Dieppe, P. The “placebo” response in osteoarthritis and its implications for clinical practice. Osteoarthritis Cartilage 17, 1255–1262 (2009).

    CAS  Google Scholar 

  133. 133

    Abhishek, A. & Doherty, M. Mechanisms of the placebo response in pain in osteoarthritis. Osteoarthritis Cartilage 21, 1229–1235 (2013).

    CAS  Google Scholar 

  134. 134

    Wojtowicz-Praga, S. Clinical potential of matrix metalloprotease inhibitors. Drugs R. D. 1, 117–129 (1999).

    CAS  Google Scholar 

Download references

Acknowledgements

T.P. received funding from the German Research Foundation (SFB1009 TP08 and PA689/7). T.P. and A.K.P. received funding from the German National Ministry of Education and Research (01EC1008D).

Author information

Affiliations

Authors

Contributions

Both authors researched the data for the article and provided a substantial contribution to discussions of the content, and contributed equally to writing the article and to review and editing of the manuscript before submission.

Corresponding author

Correspondence to Thomas Pap.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pap, T., Korb-Pap, A. Cartilage damage in osteoarthritis and rheumatoid arthritis—two unequal siblings. Nat Rev Rheumatol 11, 606–615 (2015). https://doi.org/10.1038/nrrheum.2015.95

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing