| Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by synovitis, hyperplasia of synovial membrane, neovascularization and progressive destruction of cartilage and bone. It is usually a chronic, typically life-long illness that ultimately results in disability and a shortened life expectancy.Although the etiology of RA remains unknown, most of studies have suggested that the imbalance of immune response, especially the imbalance of Th1/Th2 immune response and the over-production of proinflammatory cytokines(such as tumor necroses factor-α, IL-1β, Il-12, IL-15, IL-18, IL-6 etc.), play an important role in the pathogenesis of RA. In addition, recent studies suggest that the fibroblast-like synoviocyte(FLS) is also crucial in the initiation of pathogenesis, matainance of chronic synovitis and destruction of cartilage and bone. Synovitis, the hyperplasia of synovium, pannus formation and the destruction of cartilage and bone are the main pathohistological properties of RA. The activated FLS at the inflammatory joint can express and secrete many kinds of adhesion molecules, chemokines, proinflammatory cytokines such as vascular cell adhesion molacule-1(VCAM-1), intracellular adhesion nolecule-1(ICAM-1), macrophage chemotactic protein-1(MCP-1), macrophage inflammatory protein(MIP), IL-1, IL-6, IL-8, granulocyte-macrophage colony stimulating factor, which can recruitment the macrophage, neutrophil and lymphocyte to the affected joints, promote their activation and proliferation, and result in the development of inflammation; Thevescular endothelial growth factor(VEGF), transforming growth factor-β(TGF-β), platelet derived growth factor(PDGF), and fibroblast growth factor(FGF) they produced, can promote neovascularization and pannus formation; These cells can also produce extracellular matrix degrading enzymes, including metalloproteinases, cathepsin B, cathepsin L, cathepsin K, and aggrecanses, which are the main factors mediating the progressive destruction of the joints. The activation and proliferation of synoviocytes is the basis for all of these pathologic changes. Although there are still disagreements to the mechanism of synovial proliferation, it is generally believed that alterations in the proliferating characteristic and the defective apoptosis are the predominant causes. RA FLS exhibit many features and phenotypes of transformed cells, such as variation in size and shape , abundant of cytoplasm, prominent nucleoli, anchorage-independent growth and loss of contact inhibition, and expanssion in a monoclonal or oligoclonal manner. Tolemerase activation plays significant roles in cell proliferation and immortality, its activity is detected in RA FLS. The findings of that RA FLS co-implanted with normal human cartilage into SCID mouse matained their transformed appearance suggest that the alterations of proliferating characteristics are permanent imprinting of articular inflammatory milieu or genetic alteration. The somatic mutation of p53 tumor suppressive gene and activation of pro-oncogenes (c-myc, c-jun, c-fos) is associated with these changes. RA FLS exhibit dominant negative mutation of p53. This mutation can result in the decreased production of p21 and therefor increase the syntheses of cyclin D1, which promotes the cells into cell cycle progression and leads to the hyperplasis of synovium. In another aspect, the pro-inflammatory cytokines presented in the inflammatory joints stimulate the activation and proliferation of synovial cells, that is a alternative cause of synovial hyperplasia. Among these cytokines, TNFα is a potent stimulating agent that promote the proliferation of synovioctes, increase the secretion of cytokines and theproduction of extracellular matrix degrading enzymes. TNFα transduces its signals by binding to TNF receptors(TNFR). Studies have showed that RA FLS express TNFRs and TNFα can stimulate proliferation of RA FLS through down-regulating the expression of TNFR1 and up-regulating that of TNFR2. In addition, the act...
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