title: 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'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. 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.
authors: Geriatric Research Education and Clinical Centers, Veteran's Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors: Qian
authors: Q
authors: Wang
authors: Andrew L
authors: AL
authors: Rozelle
authors: Christin M
authors: CM
authors: Lepus
authors: Carla R
authors: CR
authors: Scanzello
authors: Jason J
authors: JJ
authors: Song
authors: D Meegan
authors: DM
authors: Larsen
authors: James F
authors: JF
authors: Crish
authors: Gurkan
authors: G
authors: Bebek
authors: Susan Y
authors: SY
authors: Ritter
authors: Tamsin M
authors: TM
authors: Lindstrom
authors: Inyong
authors: I
authors: Hwang
authors: Heidi H
authors: HH
authors: Wong
authors: Leonardo
authors: L
authors: Punzi
authors: Angelo
authors: A
authors: Encarnacion
authors: Mehrdad
authors: M
authors: Shamloo
authors: Stuart B
authors: SB
authors: Goodman
authors: Tony
authors: T
authors: Wyss-Coray
authors: Steven R
authors: SR
authors: Goldring
authors: Nirmal K
authors: NK
authors: Banda
authors: Joshua M
authors: JM
authors: Thurman
authors: Reuben
authors: R
authors: Gobezie
authors: Mary K
authors: MK
authors: Crow
authors: V Michael
authors: VM
authors: Holers
authors: David M
authors: DM
authors: Lee
authors: William H
authors: WH
authors: Robinson
mesh_terms: D000818:Animals; D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D003182:Complement C5 / Q000235:genetics / Q000378:metabolism*; D003183:Complement C6 / Q000235:genetics / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007596:Joints / Q000378:metabolism / Q000473:pathology; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology*; D040901:Proteomics / Q000379:methods; D013582:Synovial Fluid / Q000378:metabolism
chemical_list: D018957:CD59 Antigens; C539311:CD59a protein, mouse; D003182:Complement C5; D003183:Complement C6; D015938:Complement Membrane Attack Complex; D048049:Extracellular Signal-Regulated MAP Kinases; D053509:Matrix Metalloproteinase 13