The role of the adipokines visfatin and leptin in the pathogenesis of rheumatoid arthritis
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Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease, which is mainly characterized by a painful affection of multiple joints. The synovial tissue lining the joint cavity is clearly thickened in inflamed joints and activated synovial fibroblasts (SFs) align in the lining layer closely to the cartilage-bone junction. SFs can adhere to, invade into and degrade the cartilage by producing different matrixmetalloproteinases (MMPs). Visfatin and leptin belong to the group of adipokines, molecules released from adipose tissue. Visfatin has been demonstrated to function as an extracellular cytokine, but also as an intracellular enzyme regulating energy metabolism on the cellular level. Leptin on the other hand is known as a hormone regulating food intake at the level of the central nervous system. Recent studies have shown that both proteins are actively participating in the inflammatory immune response affecting arthritic joints in RA. The aim of this work was to detect both leptin and visfatin in the joints of RA patients and to investigate their influence on joint inflammation. Thus, synovial fluid and synovial tissue of RA patients were analyzed. Responses of SFs to the stimulatory effect of visfatin and leptin as well as effects of possible alterations in the cytokine microenvironment on fibroblasts and lymphocytes were studied. Leptin and visfatin are present in the synovial fluid of RA patients, whereas only visfatin was positively correlated to parameters of inflammation such as C-reactive protein (CRP). Visfatin was detectable in the synovial tissue around interstitial vessels, lymphoid aggregates and in the lining layer by immunohistochemistry. A clear change in the gene expression pattern of RASFs was induced by visfatin showing an upregulation of proinflammatory cytokines and MMPs. The most distinct change was seen for the subgroup of chemokines. Stimulation of RASFs with visfatin led to an alteration of the cytokine environment, which was chemoattractive not only for RASFs in an autocrine fashion but also for lymphocytes. Visfatin-conditioned medium increased directed fibroblast migration towards a gradient as well as undirected cell migration and therefore overall cell motility. These and other previously published results lead to the hypothesis that visfatin acts as a proinflammatory cytokine in arthritic joints by enhancing the joint-destructive potential of RASFs and by promoting their accumulation in the lining layer . In contrast, leptin did not significantly influence the gene expression profile of RASFs, neither on the RNA nor the protein levels. Therefore, leptin appears not to be a main trigger of RASF activation. Of note, results from animal models of RA showed that inhibition of the enzymatic activity of visfatin led to an amelioration of the disease. Taken together, the results of this study suggest that visfatin is an important proinflammatory cytokine, which could be a novel therapeutic target in RA.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler