Investigation of the mechanism of joint destruction in inflammatory process and the development of its prophyractic treatement by cellular and molecular biological approach

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In order to examine the localization of adhesion molecule (VLA-4, VLA-5), matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) in rheumatoid synovium, the cartilage-pannusjunction in rheumatoid arthritis (RA) were explored immunohistochemically. VLA-5 is strongly expressed on the cell surface of synovial cells contacting extracellular cartilage matrix, which is suggesting that interaction of VLA-5 and fibronectin constituting the matrix might be important in pannus formation and invasion in rheumatoid synovium. Both MMP-1 and MMP-3 are positively stained closed to the VLA-5 antigen in cartilage-pannusjunction, whereas the expression of TIMP-1 was very weak. These results may indicate that imbalance of MMP and TIMP in cartilage-pannus junction may accelerate the invasion of pannus on articular cartilage lead to joint destruction.Modulation of adhesion molecule expression on cultured synovial fibroblasts by inflammatory stimulation were also examined in order to elucidate the possibilities of the suppression of joint destruction in RA by inhibiting the expression of adhesion molecule and its function. Inflammatory cytokines such as interleukin-1β has augmented the cell attachment of human macrophage cell line U-937 to RA synovial fibroblasts. While the expression of adhesion molecules such as 1CAM-1 and VCAM-1 were enhanced by stimulation of inflammatory cytokines, the expression of VLA-5 has been stable. These results suggest that VLA-5 has not been influenced quantitively by inflammatory stimulation and functional inhibition of VLA-5 directly by antibodies might be necessary for the RA treatment in terms of the modulation of adhesion molecule expression and cell attachment.