Development of novel therapeutics for rheumatoid arthritis utilizing the adenosine deaminase inhibition

利用腺苷脱氨酶抑制开发类风湿性关节炎的新疗法

基本信息

批准号：
17591043
负责人：
KOSHIBA Masahiro
金额：
$ 2.24万
依托单位：
Hyogo College of Medicine (2006)Kobe University (2005)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

We previously reported that the elevated adenosine deaminase (ADA) activities in the joints of rheumatoid arthritis (RA) patients contribute to the pathogenesis of RA by neutralizing the anti-rheumatic properties of endogenous adenosine. In the present study, we examined the in vivo effects of ADA inhibitor on Lewis rats adjuvant-induced arthritis. The novel non-nucleoside ADA inhibitor FR242685 was daily injected into the right ankle of each rat. The development of arthritis was significantly suppressed on FR242685-treated rats in a concentration-dependent manner, while FR242685 alone did not induce arthritis. FR242685 treatment did not show any adverse effect. Radiographic analyses revealed that osteoporosis, joint space narrowing and bone destruction were all improved in arthritis rats treated with FR242685 compared with those in arthritis rats treated with saline. Histopathological analyses also revealed that FR242685 treatment improved the joint space narrowing, destruction of cartilage, proliferation of synoviocytes, infiltration of inflammatory cells, and formation of pannus. Decrease in blood and SF adenosine of arthritis rats were normalized, but not exceeded the normal level, by FR242685, which may explain the absence of adverse effects in FR242685 treatment. Concentration of IFNγ and TNF α in plasma as well as concentration of IL-6 in ankle tissue of arthritis rats treated with FR242685 were significantly lower than those of arthritis rats treated with saline. mRNA expression of IL-6 and RANKL in ankle tissue of arthritis rats treated with FR242685 was significantly lower than that of arthritis rats treated with saline. These data suggest that treatment with FR242685 improves the arthritis in vivo without any adverse effects, making the ADA inhibitor as a plausible candidate with which to develop novel therapeutics for RA.

我们之前报道过，类风湿性关节炎（RA）患者关节中腺苷脱氨酶（ADA）活性升高，通过中和内源性腺苷的抗风湿特性来促进 RA 的发病。在本研究中，我们检查了其体内效应。 ADA 抑制剂对 Lewis 大鼠佐剂诱导的关节炎的影响每天将新型非核苷 ADA 抑制剂 FR242685 注射到每只大鼠的右脚踝中。 FR242685 治疗的大鼠以浓度依赖性方式显着抑制关节炎的发展，而单独使用 FR242685 治疗不会诱发关节炎，放射线分析显示骨质疏松、关节间隙狭窄和骨质破坏均得到改善。与用盐水治疗的关节炎大鼠相比，用 FR242685 治疗的关节炎大鼠的组织病理学分析也显示，FR242685 治疗有所改善。 FR242685 使关节炎大鼠的关节间隙变窄、软骨破坏、滑膜细胞增殖、炎症细胞浸润和血管翳形成正常化，但没有超过正常水平，这可能解释了关节炎大鼠的血液和 SF 腺苷减少。 FR242685 治疗后的关节炎大鼠血浆中 IFNγ 和 TNF α 浓度以及踝关节组织中 IL-6 浓度的不良反应。用FR242685治疗的关节炎大鼠的踝关节组织中IL-6和RANKL的mRNA表达显着低于用盐水治疗的关节炎大鼠。这些数据表明用FR242685治疗改善。 ADA 抑制剂在体内对关节炎没有任何副作用，这使得 ADA 抑制剂成为开发 RA 新型疗法的合理候选者。