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Identification of a central role for complement in osteoarthritis

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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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.).

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Authors

Contributions

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.

Corresponding author

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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Wang, Q., Rozelle, A., Lepus, C. et al. Identification of a central role for complement in osteoarthritis. Nat Med 17, 1674–1679 (2011). https://doi.org/10.1038/nm.2543

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