Mechanism of synovial cell proliferation and osteoclast differentiation in an in vitro model of bone destruction of cultured rheumatoid synovium

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Rheumatoid arthritis (RA) is a chronic inflammatory arthritis characterized by bone and cartilage destruction leading to loss of joint function. Characteristic histological features of RA are hyperplasia of synovial lining cells with a dense microvasculature and infiltration of inflammatory mononuclear cells with a formation of lymphoid follicles. Osteoclast is an only bone resorbing cells in the human bone tissues and recent studies demonstrated an involvement of osteoclasts or osteoclast-like cells in the pathogenesis of focal bone erosion in RA. Two factors, receptor activator of NF-KB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) are essential for the differentiation and activation of osteoclasts. However, the precise mechanism of osteoclast differentiation in the inflamed rheumatoid synovial tissues remains to be established. Recently, we have established a novel in vitro model of bone destruction by rheumatoid synovium^<20)>. This culture system employed osteocl … More ast-like cells differentiated from RA synovial tissue without any inducers. Using the in vitro culture model of bone destruction, we sought to determine what factors are involved in the development of osteoclast-like cells from RA synovium Formation of OC-like cells in the culture of RA synovial tissue was much higher than that in the culture OA synovial tissue and cultured rheumatoid synovium produced higher level of VEGF. VEGF receptor determined imniunohistochemically was expressed on the macrophages and OC like multinucleated cells. VEGF receptor 1-Fc chimeric protein inhibited OC-like cell and pit formation in a dose-dependent manner. Osteoprotegerin (OPG) and TNF receptor II-Fc chimeric protein also inhibited OC formation, but MCSF receptor-Fc chimeric protein was not effective. The RANK peptide that binds to RANKL inhibited OC-like cell formation in the cultured RA synovium.Our data suggest that both RANKL-dependent and independent signals might be involved in the formation of osteoclasts in the in vitro model of bone destruction. In addition, VEGF might be one of the key mediators of osteoclast-mediated bone destruction by RA synovium. Inhibition of RANKL/RANK and VEGF pathway could be a new strategy for the treatment of RA. Less