Osteopontin is critically involved in rheumatoid arthritis; however, the molecular cross-talk between osteopontin and joint cell components that leads to the inflammatory joint destruction is largely unknown. We found that not only osteopontin but also tenascin-C and their common receptor, α 9 integrin, are expressed at arthritic joints. The local production of osteopontin and tenascin-C is mainly due to synovial fibroblasts and, to a lesser extent, synovial macrophages. Synovial fibroblasts and macrophages express α 9 integrin, and autocrine and paracrine interactions of α 9 integrin on synovial fibroblasts and macrophages and its ligands contribute differently to the production of proinflammatory cytokines and chemokines. α 9 integrin is also involved in the recruitment and accumulation of inflammatory cells. Inhibition of α 9 integrin function with an anti-α 9 integrin Ab significantly reduces the production of arthrogenic cytokines and chemokines and ameliorates ongoing arthritis. Thus, we identified α 9 integrin as a critical intrinsic regulator that controls the development of autoimmune arthritis.