Adenoviral transfer of cyclin-dependent kinase inhibitor genes suppresses collagen-induced arthritis in mice

In rheumatoid synovial tissues, synovial fibroblasts are activated by proin flammatory cytokines and proliferate to develop hyperplastic pannus tissues , which irreversibly damage the affected joints. We recently reported that the cyclin-dependent kinase inhibitors p16(INK4a) and p21(Cip1) are not exp ressed in vivo in rheumatoid synovial fibroblasts, but are readily inducibl e in vitro. This observation was followed by the successful treatment of ra t adjuvant arthritis by local p16(INK4n) gene transfer, showing that the in hibition of the cell cycle of the synovial cells ameliorates the arthritis. In this study, we show that another animal model of rheumatoid arthritis, murine collagen-induced arthritis, can be effectively treated by local gene transfer of p21Cip1 as well as that of p16(INK4a). Th, anti-arthritic effe cts were observed even when the treatment was conducted after the arthritis had developed. Furthermore, the effects included suppression of the expres sion of proinflammatory cytokines such as IL-1 beta, IL-6, and TNF-alpha. O ur results demonstrate that the ectopic expression of cyclin-dependent kina se inhibitors not only prevents synovial overgrowth but also ameliorates th e proinflammatory milieu in the affected joints. The induction of p21(Cip1) in rheumatoid synovial tissues by pharmacological agents may also be an ef fective strategy to treat rheumatoid arthritis.