THERAPEUTIC STRATEGY OF RHEUMATOID ARTHRITIS BY THE REGULATION OF ANTI-ONCOGENE p53 AND AN ANTI-ANGIOGENIC FACTOR.

血管生成是早期类风湿关节炎（RA）患者滑膜炎的一个特征，也被认为在类风湿滑膜增生中起着至关重要的作用。血管生成是促血管生成因子和抗血管生成因子之间的平衡。为了阐明类风湿关节炎血管生成的发病机制，我们研究了促血管生成因子包括血管内皮生长因子（VEGF）和抗血管生成因子血栓反应蛋白-1 （TSP-1）的表达。我们发现TSP-1的表达在活跃炎症的滑膜组织中被抑制，这导致促血管生成因子和抗血管生成因子的失衡。由此看来，血管生成相关因子的调控是RA治疗的候选分子靶点，尤其是在早期RA患者中。因此，我们研究了TSP-1基因在实验性关节炎模型小鼠中的引入。在预防性实验中，将TSP-1质粒预先导入胶原诱导的关节炎小鼠，可显著延缓关节炎的发作。此外，将TSP-1质粒引入已经患有胶原诱导关节炎的小鼠中，可以抑制关节炎的程度。这些结果表明，通过过度表达TSP-1抑制血管生成成功地抑制滑膜炎的进展。这些研究清楚地显示了引入TSP-1作为治疗RA的新策略的潜力。

Angiogenesis is a characteristic feature in the synovitis in patients with early rheumatoid arthritis (RA), and also is believed to have a crucial role in the proliferation of rheumatoid synovium. Angiogenesis is balanced between the pro-angiogenic factors and anti-angiogenic factors. To elucidate the pathogenesis of angiogenesis in rheumatoid arthritis, we investigated the expression of pro-angiogenic factors including vascular endothelial growth factor (VEGF) and anti-angiogenjc factor, thrombospondin-1 (TSP-1). And we showed that the expression of TSP-1 is suppressed in synovial tissue with active inflammation, and this lead to an imbalance of pro-angiogenic factors and anti-angiogenic factors. From this notion, the regulation of factors involved in the angiogenesis is a candidate of molecular target in RA therapy, especially in patients with early RA.Thus, we investigated the introduction of TSP-1 gene in the experimental arthritis model mouse. In the preventive experiments, pre-introduction of TSP-1 plasmid into mouse with collagen-induced arthritis significantly delayed the onset of arthritis. Also, introduction of TSP-1 plasmid into the mouse who have already have collagen-induced arthritis suppressed the extent of arthritis. These results showed the suppression of angiogenesis by the over-expression of TSP-1 successfully inhibit the progression of synovitis. These investigations clearly showed the potential of TSP-1 introduction as a new strategy in RA treatment.