α9β1 integrin acts as a critical intrinsic regulator of human rheumatoid arthritis

Objective. The role of the joint tissue microenvironment in the pathogenesis of human RA has recently attracted much attention. The present study investigated the roles of alpha 9 beta 1 integrin and its ligands in synovial specimens of human RA patients in generating the unique human arthritic tissue microenvironment. Methods. Synovial fibroblasts and macrophages were isolated from the synovial tissue of patients with RA or OA. The expression of alpha 9 beta 1 integrin was analysed using FACS with multicolour staining. The production of MMPs and proinflammatory cytokines was analysed in cultures of synovial fibroblasts and macrophages with alpha 9 beta 1 integrin ligands. Results. Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed alpha 9 beta 1 integrins, a common receptor for osteopontin and tenascin-C. In the synovial fibroblasts of RA, the amount of tenascin-C protein produced was much greater than that of osteopontin in synovial fibroblasts of RA. Importantly, autocrine and paracrine interactions of alpha 9 beta 1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-alpha and IL-1 beta in synovial macrophages. Conclusion. These findings indicate that autocrine and paracrine interaction of alpha 9 beta 1integrin and tenascin-C in the joint tissue microenvironment contributes to the pathogenesis of RA. Therefore alpha 9 beta 1 integrin may become a potential therapeutic target for RA.