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

我们以前报道过，类风湿关节炎（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而促进RA的发病。在本研究中，我们研究了ADA抑制剂对刘易斯大鼠关节炎的体内作用。每天将新型非核苷ADA抑制剂FR 242685注射到每只大鼠的右踝。在FR 242685处理的大鼠中，关节炎的发展以浓度依赖性方式被显著抑制，而单独的FR 242685不诱导关节炎。FR 242685治疗未显示任何不良反应。放射学分析显示，与用盐水治疗的关节炎大鼠相比，用FR 242685治疗的关节炎大鼠的骨质疏松症、关节间隙狭窄和骨破坏都得到改善。组织学分析还显示，FR 242685治疗改善了关节间隙变窄、软骨破坏、滑膜细胞增殖、炎性细胞浸润和血管翳形成。FR 242685使关节炎大鼠的血液和SF腺苷减少正常化，但未超过正常水平，这可以解释FR 242685治疗中无不良反应。FR 242685治疗组大鼠血浆中IFNγ、TNF α浓度及踝关节组织中IL-6浓度均显著低于生理盐水治疗组。FR 242685治疗的关节炎大鼠踝关节组织中IL-6和RANKL的mRNA表达显著低于盐水治疗的关节炎大鼠。这些数据表明，用FR 242685治疗改善了体内关节炎而没有任何副作用，使得ADA抑制剂成为开发RA新疗法的合理候选物。

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.