It has been shown that osteopontin (OPN) is critically involved in various Th1 type immune-mediated disorders such as rheumatoid arthritis (RA) and multiple sclerosis. In this study, we demonstrated that the expression of both OPN and tenascin-C (TN-C), and its common receptor, α9 integrin are up-regulated at the pathological foci of autoimmune arthritis. The local production of OPN and TN-C in arthritic joints is due to mainly synovial fibroblsts and to the lesser extent synovial macrophages. Majority of synovial fibroblasts and a subpopulation of synovial macrophages express α9 integrin. Importantly, autocrine and paracrine interactions of α9 integrin on synovial macrophages and fibroblasts and its ligands differently contribute to the production of pro-inflammatory cytokines and chemokines. α9 integrin is also involved in the recruitment and accumulation of inflammatory cells, through interaction with vascular cell adhesion molecule-1 (VCAM-1). Inhibition of α9 integrin function with an inhibitory anti-α9 integrin antibody significantly reduces production of arthrogenic cytokines and chemokines and ameliorates on-going arthritis. Thus, we identified α9 integrin as a critical intrinsic regulator that control the development of autoimmune arthritis. These results suggest that α9 integrin serves as a novel therapeutic target for the treatment of autoimmune disorders including RA.