Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts

Rheumatoid arthritis (RA) is characterized by a chronic inflammation of the synovial joints resulting from hyperplasia of synovial fibroblasts and inf iltration of lymphocytes, macrophages, and plasma cells, arl of which manif est signs of activation. Recent studies have revealed the essential role of osteoclasts in joint destruction in RA. Src family tyrosine kinases are im plicated in various intracellular signaling pathways, including mitogenic r esponse to growth factors in fibroblasts, activation of lymphocytes, and os teoclastic bone resorption. Therefore, inhibiting Src activity can be a goo d therapeutic strategy to prevent joint inflammation and destruction in RA. We constructed an adenovirus vector carrying the csk gene, which negativel y regulates Src family tyrosine kinases. Csk overexpression in cultured rhe umatoid synoviocytes remarkably suppressed Src kinase activity and reduced their proliferation rate and IL-6 production. Bone-resorbing activity of os teoclasts tvas strongly inhibited by Csk overexpression. Furthermore, local injection of the virus into rat ankle joints with adjuvant arthritis not o nly ameliorated inflammation but suppressed bone destruction. In conclusion , adenovirus-mediated direct transfer of the csk gene is useful in repressi ng bone destruction and inflammatory reactions, suggesting the involvement of Src family tyrosine kinases in arthritic joint breakdown and demonstrati ng the feasibility of intervention in the kinases for gene therapy in RA.