Synovial lining hyperplasia is a characteristic of rheumatoid arthritis, though the mechanism of increased synovial cell number remains largely unknown. Analysis of human RA synovial tissues (ST) sections revealed increased rates of fibroblast-like synoviocyte (FLS) proliferation and low rates of apoptosis, though the functional significance of reduced apoptosis remains to be elucidated. However, analysis of the rates of in-vivo proliferation and apoptosis are limited in human-STs as tissue sections were taken late in the course of the disease. Additionally, Bcl-2, an apoptotic antagonist and cell cycle modulator has also been identified in proliferating human RA- FLSs. Thus, we will determine the frequencies of apoptosis and proliferation and how they correlate with Bcl-2 expression in the rat model of experimental arthritis. Recently, adenoviral mediated delivery of Fas ligand, a known apoptotic inducer ameliorated arthritis in severe combined immunodeficiency-RA mice, suggesting that enhancing the rate of apoptosis by gene therapy may be a potential effective therapy. A caveat to Ad-Fas ligand therapy is that high levels of Fas ligand is cytotoxic to many tissues of the body, thus development of other genes to be delivered to the RA joint is essential. In this proposal we describe studies to determine whether adenoviral mediated delivery of Bcl-2 ribozyme is efficient in ameliorating adjuvant-induced arthritis in rats. The expected outcome may potentially be the inhibition of fibroblast proliferation and increased apoptosis, leading to remission in animal models of experimental arthritis.
