Prophylactic Adenovirus-Mediated PTEN Gene Therapy Suppresses Rat Collagen-Induced Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic joint disease characterized by hyperplasia of synovium, excessive infiltration of mononuclear cells, and extensive destruction of the articular cartilage. Hyperplasia of synovium leads to formation of pannus which destroys cartilage and bone in the affected joint. Angiogenesis, the formation of new blood vessels, is one of the earliest histopathologic findings in RA and appears to be necessary for pannus development. In this study, an adenoviral vector encoding PTEN (phosphatase and tensin homology deleted from chromosome 10), designated Ad-PTEN, was generated for gene therapy in the rat collagen-induced arthritis model. PTEN is a tumor suppressor that antagonizes the PI3 kinase (PI3K) pathway. Overexpression of PTEN suppresses cell proliferation and enhances apoptosis. Furthermore, PTEN can regulate VEGF-mediated endothelial cellular responses and angiogenesis. We observed that Ad-PTEN treatment reduced VEGF production, cell proliferation and enhanced apoptosis in the synovial fibroblasts from RA patients (RASF), whereas Ad-LacZ, a control adenoviral vector encoding β-galactosidase, had no effects. In cultured endothelial cells, PTEN overexpression also suppressed the cell proliferation. Moreover, prophylactic intraarticular injection of Ad-PTEN into the ankle joints of arthritic rats reduced the severity of arthritis, compared with those treated with Ad-LacZ. Decreased microvessel density within the joint tissue was observed in the Ad-PTEN-treated group compared with the Ad-LacZ-treated group. Taken together, these results suggest that the prophylactic effects of Ad-PTEN in CIA may be attributable, at least in part, to the down-regulation of cell proliferation in RASF and endothelial cells, and VEGF secretion in RASF.

Date of Award	2006
Original language	English
Supervisor	Ai-Li Shiau (Supervisor) & Chrong-Reen Wang (Supervisor)