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

通过抗癌基因 p53 和抗血管生成因子的调节来治疗类风湿性关节炎。

• 批准号: 11670460
• 负责人: YAMANAKA Hisashi
• 金额: $ 1.79万
• 依托单位: TOKYO WOMEN'S MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670460/
• 关键词: RHEUMATOID ARTHRITIS; ANGIOGENESIS; SYNOVITIS; THROMBOSPONDIN-1; COLLAGEN-INDUCED ARTHRITIS; TSP-1

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.

血管生成是早期类风湿性关节炎（RA）滑膜炎的特征性表现，也被认为在类风湿性关节炎滑膜增生中起重要作用。血管生成在促血管生成因子和抗血管生成因子之间平衡。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小板反应蛋白-1（TSP-1）的表达。我们发现，TSP-1的表达在炎症活动的滑膜组织中受到抑制，这导致了促血管生成因子和抗血管生成因子的失衡。因此，调控参与血管生成的因子是RA治疗的一个候选分子靶点，特别是在早期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导入。在预防性实验中，预先将TSP-1质粒导入患有胶原诱导的关节炎的小鼠中显著延迟了关节炎的发作。此外，将TSP-1质粒导入已经患有胶原诱导性关节炎的小鼠中抑制了关节炎的程度。这些结果表明通过TSP-1的过表达抑制血管生成成功地抑制了滑膜炎的进展。这些研究清楚地显示了TSP-1作为RA治疗新策略的潜力。