Citrullination of fibronectin modulates synovial fibroblast behavior

Arthritis research & therapy (Impact Factor: 3.75). 11/2012; 14(6):R240. DOI: 10.1186/ar4083
Source: PubMed


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. 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.
To 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.
Normal 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.
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.

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Available from: David A Bennin, Jan 20, 2015
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    • "Citrullinated fibrinogen and citrullinated collagen type II are more immunogenic and arthritogenic in mouse models of arthritis, and citrullinated fibrinogen activates macrophages more than unmodified fibrinogen [10]. Recently, citrullination of fibronectin was shown to alter synovial fibroblast behavior [14]. Sokolove and colleagues [15] found that fragments of citrullinated proteins can bind to ACPAs and cause activation of macrophages and antigen-presenting cells. "
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    ABSTRACT: Citrullination and the immune response to citrullinated proteins have been fundamental for the early recognition of rheumatoid arthritis by serological tests and a better understanding of its pathophysiology. In the first years after the initial publications, the focus was on the antibodies directed to citrullinated proteins. It is now realized that citrullinating enzymes and citrullinated proteins may have important roles in the maintenance of the inflammatory processes in the joints. There is also accumulating evidence for a direct role of citrullination in tissue destruction in the rheumatoid synovium. Here we will discuss the development and importance of anti-citrullinated protein antibodies in rheumatoid arthritis as well as recent findings implicating citrullination in the pathophysiology of rheumatoid arthritis.
    Arthritis research & therapy 01/2014; 16(1):103. DOI:10.1186/ar4458 · 3.75 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) synovium is characterised not only by increases in number and activity of lymphocytes and macrophages, but also of resident mesenchymal cells known as fibroblast-like synoviocytes (FLS). Originally thought of as passive structural cells, research over two decades has demonstrated the capacity for autonomous contributions of FLS to RA inflammation as effector cells producing cytokines and other pro-inflammatory mediators. More recently, as understanding of RA as a genuine autoimmune disease characterised by immunity to citrullinated proteins has grown, so the potential involvement of FLS in even proximal aspects of initiation and maintenance of abnormal adaptive immune responses has come to light. In this review we take a step-by-step approach to the role of FLS, considering their contribution to the phenomena, as currently understood, in RA pathogenesis. It can be concluded that significant evidence favours a broad role for FLS in synovial immunity, as well as inflammation.
    Current Opinion in Pharmacology 04/2013; 13(4). DOI:10.1016/j.coph.2013.04.001 · 4.60 Impact Factor
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    ABSTRACT: One of the most important serological discoveries in rheumatology in recent years has been the characterization of autoantigens in rheumatoid arthritis (RA) containing the amino acid citrulline. There are many citrullinated proteins in the inflamed RA synovium. Rheumatoid factor (RF), which is the immunologic hallmark of RA, is not specific for RA, as it is found in 5% of healthy individuals and in 10-20% of those over the age of 65 years. RFs are of low titer in early disease stages when a clear diagnosis is often not yet possible; But anti-citrullinated protein antibodies (ACPAs) can be found early in the disease course of RA, even years before the onset of clinical symptoms. The identification of citrullinated epitopes led to the development of the first and later second generation anti-cyclic citrullinated peptide (anti-CCP) antibody assays. Anti-CCP2 antibody has shown a specificity of 98% in sera from patients with established RA and 96% in sera from subjects with early RA. Anti-CCP can predict erosive disease, therefore could be a good serological marker for RA diagnosis.
    International Journal of Rheumatic Diseases 08/2013; 16(4):379-86. DOI:10.1111/1756-185X.12129 · 1.47 Impact Factor
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