Citrullination is the conversion of the arginine residues of a protein to citrulline

Citrullination is the conversion of the arginine residues of a protein to citrulline. synovial fibroblasts have impaired adhesion, spreading, migration, and integrin-mediated phosphorylation of focal adhesion kinase YAP1 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. Conclusion Citrullination 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. Introduction Rheumatoid arthritis is a chronic, debilitating arthritis characterized by painful joint inflammation and destructive erosions. 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]. ACPAs are specific for rheumatoid arthritis and predict severe, erosive arthritis [3]. Despite the rapidly increasing volume of information about ACPAs, the role of the citrullinated proteins themselves is less clear. Citrullination is the conversion of a protein’s arginine residues to citrulline, resulting in a loss of charge and often abnormal protein conformation and function. Citrullination is catalyzed by a family of enzymes called peptidyl arginine deiminases (PADs). Protein citrullination in the rheumatoid joint is increased [4] and PAD4 and PAD2 are upregulated BMX-IN-1 in rheumatoid synovium [5,6] and synovial fluid [4]. Inflammation appears to play a role in the level of citrullination since local administration of glucocorticoids reduces citrullination in the rheumatoid joint [7]. Despite the specificity of ACPAs to rheumatoid arthritis, however, 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]. The role of protein citrullination in rheumatoid arthritis is enigmatic, although most evidence supports a pathologic role. Citrullinated fibrinogen [10] and citrullinated collagen type II [11] are more immunogenic and arthritogenic in mouse models of arthritis, and citrullinated fibrinogen activates macrophages more than unmodified fibrinogen [12]. Further, treatment with Cl-amidine, a pan-PAD inhibitor, improves collagen-induced arthritis [13]. In contrast, citrullinated CXCL10, CXCL11 [14], IL-8 [15], and CXCL12 [16] lose inflammatory function, but these proteins have not been shown to be citrullinated in rheumatoid arthritis. Some proteins that have been shown to be citrullinated in rheumatoid arthritis include type II collagen, vimentin, fibrinogen, and fibronectin [17,18]. Fibronectin is interesting because it modulates numerous cellular behaviors including migration, adhesion, invasion, and survival. More specific to rheumatoid arthritis, fibronectin is deposited on the surface of articular cartilage in BMX-IN-1 the rheumatoid joint [19] and increases the ability of synovial fibroblasts to adhere to cartilage [20]. Synovial fibroblasts are cells that normally line the joint. These fibroblasts play a significant role in rheumatoid arthritis by increasing in number as part of a pannus and by degrading cartilage and bone using matrix metalloproteases and invasive structures called invadopodia [21]. Synovial fibroblasts also can migrate in the bloodstream to invade distant cartilage in mouse models [22], which may explain how multiple joints are involved in rheumatoid arthritis. Fibronectin plays an important role in synovial fibroblast behavior. Synovial fibroblasts express the integrins 51 and v3, which are BMX-IN-1 important for fibronectin binding [23], and fibronectin is present throughout the pannus [24]. Further, fibronectin mediates synovial fibroblast adhesion to cartilage, stabilizes invadopodia [25], and modulates matrix metalloprotease production [26]. Despite the importance of fibronectin in synovial fibroblast and arthritis pathology, almost nothing.