Identification of a central role for complement in osteoarthritis

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Abstract

Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'1. Although low-grade inflammation is detected in osteoarthritis, its role is unclear2,3,4. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

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Figure 1: Complement components are aberrantly expressed and activated in human osteoarthritic joints.
Figure 2: The complement cascade, acting through its MAC effector arm, is crucial for the development of osteoarthritis in three different mouse models.
Figure 3: C5 deficiency protects against the progressive development of osteoarthritic joint pathology and gait dysfunction.
Figure 4: Cartilage ECM components can induce MAC formation, and MAC induces chondrocyte expression of inflammatory and catabolic molecules.

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References

  1. 1

    Felson, D.T. Clinical practice. Osteoarthritis of the knee. N. Engl. J. Med. 354, 841–848 (2006).

  2. 2

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

  3. 3

    Pelletier, J.P., Martel-Pelletier, J. & Abramson, S.B. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 44, 1237–1247 (2001).

  4. 4

    Hill, C.L. et al. Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Ann. Rheum. Dis. 66, 1599–1603 (2007).

  5. 5

    Gobezie, R. et al. High abundance synovial fluid proteome: distinct profiles in health and osteoarthritis. Arthritis Res. Ther. 9, R36 (2007).

  6. 6

    Kemper, C. & Atkinson, J.P. T-cell regulation: with complements from innate immunity. Nat. Rev. Immunol. 7, 9–18 (2007).

  7. 7

    Cooke, T.D., Bennett, E.L. & Ohno, O. The deposition of immunoglobulins and complement in osteoarthritic cartilage. Int. Orthop. 4, 211–217 (1980).

  8. 8

    Corvetta, A. et al. Terminal complement complex in synovial tissue from patients affected by rheumatoid arthritis, osteoarthritis and acute joint trauma. Clin. Exp. Rheumatol. 10, 433–438 (1992).

  9. 9

    Cooke, T.D. Significance of immune complex deposits in osteoarthritic cartilage. J. Rheumatol. 14 (Spec No), 77–79 (1987).

  10. 10

    Kamekura, S. et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 13, 632–641 (2005).

  11. 11

    Englund, M. & Lohmander, L.S. Risk factors for symptomatic knee osteoarthritis fifteen to twenty-two years after meniscectomy. Arthritis Rheum. 50, 2811–2819 (2004).

  12. 12

    Ooi, Y.M. & Colten, H.R. Genetic defect in secretion of complement C5 in mice. Nature 232, 207–208 (1979).

  13. 13

    Huber-Lang, M. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12, 682–687 (2006).

  14. 14

    Banda, N.K. et al. Mechanisms of effects of complement inhibition in murine collagen-induced arthritis. Arthritis Rheum. 46, 3065–3075 (2002).

  15. 15

    Banda, N.K. et al. Targeted inhibition of the complement alternative pathway with complement receptor 2 and factor H attenuates collagen antibody-induced arthritis in mice. J. Immunol. 183, 5928–5937 (2009).

  16. 16

    Glasson, S.S. In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr. Drug Targets 8, 367–376 (2007).

  17. 17

    Glasson, S.S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).

  18. 18

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

  19. 19

    Happonen, K.E. et al. Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis. Arthritis Rheum. 62, 3574–3583 (2010).

  20. 20

    Neidhart, M. et al. Small fragments of cartilage oligomeric matrix protein in synovial fluid and serum as markers for cartilage degradation. Br. J. Rheumatol. 36, 1151–1160 (1997).

  21. 21

    Scanzello, C.R., Plaas, A. & Crow, M.K. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr. Opin. Rheumatol. 20, 565–572 (2008).

  22. 22

    Sofat, N. Analysing the role of endogenous matrix molecules in the development of osteoarthritis. Int. J. Exp. Pathol. 90, 463–479 (2009).

  23. 23

    Sjöberg, A., Onnerfjord, P., Morgelin, M., Heinegard, D. & Blom, A.M. The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q. J. Biol. Chem. 280, 32301–32308 (2005).

  24. 24

    Bohana-Kashtan, O., Ziporen, L., Donin, N., Kraus, S. & Fishelson, Z. Cell signals transduced by complement. Mol. Immunol. 41, 583–597 (2004).

  25. 25

    Scanzello, C.R. et al. Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms. Arthritis Rheum. 63, 391–400 (2011).

  26. 26

    Attur, M. et al. Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor. J. Immunol. 181, 5082–5088 (2008).

  27. 27

    Badea, T.D. et al. Sublytic terminal complement attack induces c-fos transcriptional activation in myotubes. J. Neuroimmunol. 142, 58–66 (2003).

  28. 28

    Rus, H.G., Niculescu, F. & Shin, M.L. Sublytic complement attack induces cell cycle in oligodendrocytes. J. Immunol. 156, 4892–4900 (1996).

  29. 29

    Kraus, S., Seger, R. & Fishelson, Z. Involvement of the ERK mitogen-activated protein kinase in cell resistance to complement-mediated lysis. Clin. Exp. Immunol. 123, 366–374 (2001).

  30. 30

    Litherland, G.J. et al. Protein kinase C isoforms ζ and ι mediate collagenase expression and cartilage destruction via STAT3- and ERK-dependent c-fos induction. J. Biol. Chem. 285, 22414–22425 (2010).

  31. 31

    Daiger, S.P. Genetics. Was the Human Genome Project worth the effort? Science 308, 362–364 (2005).

  32. 32

    Rogers, J. et al. Complement activation by β-amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 89, 10016–10020 (1992).

  33. 33

    Huber, R. et al. Identification of intra-group, inter-individual, and gene-specific variances in mRNA expression profiles in the rheumatoid arthritis synovial membrane. Arthritis Res. Ther. 10, R98 (2008).

  34. 34

    Irizarry, R.A. et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003).

  35. 35

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

  36. 36

    Zhou, W. et al. Predominant role for C5b-9 in renal ischemia/reperfusion injury. J. Clin. Invest. 105, 1363–1371 (2000).

  37. 37

    Holt, D.S. et al. Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria. Blood 98, 442–449 (2001).

  38. 38

    Frei, Y., Lambris, J.D. & Stockinger, B. Generation of a monoclonal antibody to mouse C5 application in an ELISA assay for detection of anti-C5 antibodies. Mol. Cell. Probes 1, 141–149 (1987).

  39. 39

    Gabriel, A.F., Marcus, M.A., Honig, W.M., Walenkamp, G.H. & Joosten, E.A. The CatWalk method: a detailed analysis of behavioral changes after acute inflammatory pain in the rat. J. Neurosci. Methods 163, 9–16 (2007).

  40. 40

    Chen, Y. et al. Terminal complement complex C5b-9–treated human monocyte-derived dendritic cells undergo maturation and induce Th1 polarization. Eur. J. Immunol. 37, 167–176 (2007).

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Acknowledgements

These studies were supported by a Rehabilitation Research and Development Merit Award from the Department of Veterans Affairs and the US National Heart, Lung, and Blood Institute Proteomics Center contract N01 HV 28183 (W.H.R.); a Northern California Chapter Arthritis Foundation Postdoctoral Fellowship Award (A.L.R.); a New York Chapter Arthritis Foundation/Merck Osteoarthritis Research Fellowship Award, the Atlantic Philanthropies, the American College of Rheumatology Research and the Education Fund, the Association of Specialty Professors and the US National Institute of Arthritis, Musculoskeletal and Skin Diseases Mentored Clinical Scientist Research Career Development Award K08 AR057859 (C.R.S.); US National Institute of Neurological Disorders and Stroke P30 Center Core grant NS069375 (M.S.); US National Institutes of Health training grant T32 AR007530 (S.Y.R.); National Institutes of Health R01 AR051749 (V.M.H.); and the Frankenthaler and Kohlberg Foundations (M.K.C.).

Author information

A.L.R. and W.H.R. initiated the investigation of complement in osteoarthritis, and Q.W. conducted key studies. Q.W., A.L.R., D.M. Larsen, H.H.W. and W.H.R. conducted the studies of osteoarthritis in mouse models. A.E., A.L.R. and M.S. performed the gait analysis studies. Q.W. and H.H.W. performed the in vitro MAC deposition experiments. C.M.L. and J.J.S. performed the immunohistochemical analyses of cartilage. J.F.C., G.B., S.Y.R., L.P., S.R.G., R.G. and D.M. Lee conducted or contributed to the proteomic analysis of osteoarthritic synovial fluid. S.Y.R. and D.M. Lee performed the ELISA analysis of osteoarthritic and healthy synovial fluids. C.R.S. and M.K.C. performed the gene expression analysis of the synovium, and G.B., R.G. and D.M. Lee contributed to the analysis of these data sets. A.L.R., C.M.L., J.J.S. and I.H. performed the in vitro complement activation and stimulation assays using samples provided by S.B.G. V.M.H., J.M.T. and N.K.B. provided the antibody specific to C5 and the CR2-fH fusion protein. T.W.-C. provided the C6 and Cd59a−/− mice. V.M.H., T.M.L. and D.M. Lee provided scientific input. T.M.L., A.L.R. and W.H.R. wrote the manuscript, and Q.W., C.R.S., T.W.-C., S.R.G., M.K.C., V.M.H. and D.M. Lee edited the manuscript. All authors analyzed the data and approved the final manuscript.

Correspondence to William H Robinson.

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Competing interests

D.M. Lee is currently employed by Novartis Pharma. D.M. Lee and R.G. own equity in Synostics. J.M.T. and V.M.H. are consultants for Alexion Pharmaceuticals.

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Supplementary Methods, Supplementary Figures 1–6 and Supplementary Table 1 (PDF 650 kb)

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