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 antiinflammatory 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 TGFbeta in the synovial tissue.


CONCLUSIONS
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.
Jou
I-Ming
IM
Department of Biochemistry, National Cheng Kung University Medical College, 1 Dashiue Road, Tainan 701, Taiwan.
Shiau
Ai-Li
AL
Chen
Shih-Yao
SY
Wang
Chrong-Reen
CR
Shieh
Dar-Bin
DB
Tsai
Ching-Shan
CS
Wu
Chao-Liang
CL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control* / Q000628:therapy*; D001175:Arthrography; D001808:Blood Vessels / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors; D007270:Injections, Intra-Articular; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000098:blood supply; D019700:Thrombospondin 1 / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007375:Interleukin-1; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A