Thrombospondin 1 as an effective gene therapeutic strategy in collagen-induced arthritis

Objective. Because thrombospondin 1 (TSP-1) inhibits angiogenesis and activates latent transforming growth factor beta (TGFbeta), a potent immunosuppressive and antinflammatory cytokine, we investigated the prophylactic and therapeutic effects of TSP-1 gene transfer in the collagen-induced arthritis (CIA) model in rats. Methods. Adenoviral vectors encoding mouse TSP-1 (AdTSP-1) or beta-galactosidase (AdLacZ) as the control were administered by intraarticular injection into CIA rats. The treated ankles were assessed clinically, radiographically, and histologically. Furthermore, expression levels of TSP-1, TGFbeta, vascular endothelial growth factor (VEGF), and interleukin-1beta (IL-1beta) were examined in the synovial tissue. Results. Intraarticular administration of AdTSP-1 reduced the severity of CIA as revealed by examination of the clinical, radiographic, and histologic aspects. Rats treated with AdTSP-1, as compared with AdLacZ-treated controls, were found to have fewer blood vessels (mean +/- SEM 21.0 +/- 0.6 versus 45.3 +/- 2.3/mm(2); P < 0.001) and lower production of VEGF (17 +/- 4 versus 45 +/- 10 pg/mg of total protein; P < 0.05) and IL-1beta (374 +/- 41 versus 526 +/- 39 pg/mg of total protein; P < 0.05), as well as higher levels of TSP-1 and TGF beta in the synovial tissue. Conclusion. Direct intraarticular administration of adenoviral vectors encoding TSP-1 significantly ameliorated the clinical course of CIA, accompanied by reduction of synovial hypertrophy and fewer blood vessels. These results suggest that TSP-1 gene therapy may have therapeutic potential for the management of rheumatoid arthritis.