Identification of a central role for complement in osteoarthritis

• Published in: Nature medicine Vol. 17; no. 12; pp. 1674 - 1679
• Main Authors: Wang, Qian, Rozelle, Andrew L, Lepus, Christin M, Scanzello, Carla R, Song, Jason J, Larsen, D Meegan, Crish, James F, Bebek, Gurkan, Ritter, Susan Y, Lindstrom, Tamsin M, Hwang, Inyong, Wong, Heidi H, Punzi, Leonardo, Encarnacion, Angelo, Shamloo, Mehrdad, Goodman, Stuart B, Wyss-Coray, Tony, Goldring, Steven R, Banda, Nirmal K, Thurman, Joshua M, Gobezie, Reuben, Crow, Mary K, Holers, V Michael, Lee, David M, Robinson, William H
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2011; Nature Publishing Group
• Subjects: 631/250/2501; 631/61/475; 692/420/256; 692/699/1670/407; Animals; Arthritis; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cartilage; Cartilage - metabolism; Cartilage - pathology; Causes of; CD59 Antigens - genetics; CD59 Antigens - metabolism; Chondrocytes - metabolism; Chondrocytes - pathology; Complement C5 - genetics; Complement C5 - metabolism; Complement C6 - genetics; Complement C6 - metabolism; Complement Membrane Attack Complex - metabolism; Complement system; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Humans; Infectious Diseases; Inflammatory diseases; Joints - metabolism; Joints - pathology; letter; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 13 - metabolism; Membranes; Metabolic Diseases; Mice; Mice, Knockout; Molecular Medicine; Neurosciences; Osteoarthritis; Osteoarthritis - metabolism; Osteoarthritis - pathology; Pathogenesis; Physiological aspects; Proteomics - methods; Synovial Fluid - metabolism
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2543

Osteoarthritis, the breakdown of cartilage in synovial joints, has long been viewed as the result of 'wear and tear', but this report shows that dysregulation of the complement system has an active role in the pathogenesis of this disease. 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 unclear 2 , 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.