Abstract
IntroductionRheumatoid arthritis is an autoimmune arthritis characterized by joint destruction. Anti-citrullinated protein antibodies are pathologic in rheumatoid arthritis, but the role of the citrullinated proteins themselves is much less clear. Citrullination is the conversion of the arginine residues of a protein to citrulline. In the inflamed rheumatoid joint there is increased protein citrullination. Several proteins are citrullinated in rheumatoid arthritis, including collagen type II, fibrinogen, and fibronectin. Fibronectin is thought to mediate the adhesion of joint-invading synovial fibroblasts to the rheumatoid cartilage in addition to regulating other synovial fibroblast functions. However, the effect of citrullinated fibronectin on synovial fibroblasts is unknown.MethodsTo investigate the effect of citrullinated fibronectin on synovial fibroblast behavior, we cultured normal murine, arthritic murine, and human rheumatoid synovial fibroblasts. We then compared several synovial fibroblast functions in the presence of fibronectin versus citrullinated fibronectin. We assessed adhesion with time-lapse microscopy, migration with transwell assays, focal adhesion kinase and paxillin phosphorylation by western blot, and focal matrix degradation by fluorescent gelatin degradation.ResultsNormal synovial fibroblasts have impaired adhesion, spreading, migration, and integrin-mediated phosphorylation of focal adhesion kinase and paxillin on citrullinated fibronectin. Murine arthritic and human rheumatoid synovial fibroblasts also have impaired adhesion and spreading on citrullinated fibronectin, but focal matrix degradation is unaffected by citrullinated fibronectin.ConclusionCitrullination of fibronectin alters synovial fibroblast behavior and may affect how these cells adhere to and invade the joint and travel through the bloodstream. This work suggests an important role for the interaction of synovial fibroblasts with citrullinated matrix in the pathophysiology of rheumatoid arthritis.
Highlights
Rheumatoid arthritis is an autoimmune arthritis characterized by joint destruction
This work suggests an important role for the interaction of synovial fibroblasts with citrullinated matrix in the pathophysiology of rheumatoid arthritis
The key to this finding was the identification of anti-citrullinated protein antibodies (ACPAs), which contribute to arthritis by forming immune complexes that are deposited in the joint [1] and by activating complement [2]
Summary
Rheumatoid arthritis is an autoimmune arthritis characterized by joint destruction. Anti-citrullinated protein antibodies are pathologic in rheumatoid arthritis, but the role of the citrullinated proteins themselves is much less clear. Rheumatoid arthritis has long been known to be an inflammatory arthritis, but only recently has it been shown to be a true autoimmune disease with an immune response generated against self-antigens The key to this finding was the identification of anti-citrullinated protein antibodies (ACPAs), which contribute to arthritis by forming immune complexes that are deposited in the joint [1] and by activating complement [2]. Despite the specificity of ACPAs to rheumatoid arthritis, citrullination is a more generalized phenomenon - with increased citrullination seen in the synovial fluid of inflamed joints affected by spondyloarthropathy [4] as well as in inflamed muscle in myositis and [8] myelin basic protein in multiple sclerosis [9]
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