Cas-L/NEDD9 is a cytoplasmic docking protein downstream of beta 1 integrin-mediated signaling pathway and is essential for cellular migration and beta 1 integrin-mediated costimulation of T cells. We previously found that increased number of Cas-L positive leukocytes migrated into the inflamed joints of HTLV-I tax transgenic mice which spontaneously develop polyarthritis, suggesting a role of Cas-L in rheumatoid arthritis (RA) pathophysiology. Our current study expanded these findings on the role of Cas-L/NEDD9 in the development of RA by analyzing the pathophysiological changes in a Nedd9(-1-) mouse collagen-induced arthritis (CIA) model. Nedd9(-1-) mice exhibited a decrease in arthritis severity as compared to Nedd9(+/+) mice. In addition, as being conducted bone marrow transplantation experiments with a CIA model, Nedd9(-1-) -> Nedd9(+1+) transplant showed a decrease in the incidence and severity score of arthritis, compared to those of Nedd9(+/+) -> Nedd9(-/-) transplant. For analysis of serum levels of various cytokines, IL-1 beta, IL-6, IL-17, THE-alpha, IFN-gamma and anti-collagen antibody were decreased, while IL-4 and IL-10 levels were increased, in Nedd9-1- mice as compared to those in Nedd9(+/+) mice. Furthermore, collagen-mediated cellular responses of lymphocytes isolated from spleen or affected lymph nodes of Nedd9(-/-) mice were reduced. Our results strongly suggest that Cas-L/NEDD9 plays a pivotal role in the pathophysiology of CIA, and that Cas-L/NEDD9 may be a potential molecular target for the treatment of RA. (C) 2015 Elsevier Inc. All rights reserved.