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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591043/
• 关键词: rheumatoid arhtritis; adenosine receptors; adenosine deaminase; methotrexate; rat adjuvant arthritis; animal model; proinflammatory cytokines; osteoclasts; ラットアジバント関節炎

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，从而促进 RA 的发病机制。在本研究中，我们检查了 ADA 抑制剂对 Lewis 大鼠佐剂诱导的关节炎的体内作用。每天将新型非核苷 ADA 抑制剂 FR242685 注射到每只大鼠的右脚踝处。 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不会诱导关节炎。 FR242685治疗没有显示出任何不良反应。放射线分析显示，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骨质疏松、关节间隙狭窄和骨质破坏均得到改善。组织病理学分析还显示，FR242685治疗改善了关节间隙变窄、软骨破坏、滑膜细胞增殖、炎症细胞浸润和血管翳形成。 FR242685 使关节炎大鼠的血液和 SF 腺苷减少正常化，但没有超过正常水平，这可以解释 FR242685 治疗中没有不良反应的原因。 FR242685治疗的关节炎大鼠血浆中IFNγ和TNFα的浓度以及踝关节组织中IL-6的浓度显着低于用盐水治疗的关节炎大鼠。 FR242685处理的关节炎大鼠踝关节组织中IL-6和RANKL的mRNA表达量显着低于生理盐水处理的关节炎大鼠。这些数据表明，FR242685 治疗可改善体内关节炎，且没有任何副作用，使得 ADA 抑制剂成为开发 RA 新型疗法的合理候选者。

项目成果

関節リウマチの血清マーカー

类风湿性关节炎的血清标志物

• 发表时间: 2006
• 期刊: 臨床リウマチ 18・4
• 作者: Hirano T. et al.;Hirano T. et al.;Arimitsu J. et al.;Ouyang X. et al.;Inaba M. et al.;小柴 賢洋
• 通讯作者: 小柴 賢洋

Aberrant Over-expression of Adenosine Deaminase and its Significance on Rheumatoid Arthritis

腺苷脱氨酶异常过度表达及其在类风湿性关节炎中的意义

• 发表时间: 2005
• 期刊: Rinsho Byori 53(8)
• 作者: Nakashima Y;et al.;Masahiro Koshiba
• 通讯作者: Masahiro Koshiba

Serological Markers for the Diagnosis and Activity Assessment of Rheumatoid Arthritis.

用于类风湿关节炎诊断和活动评估的血清学标志物。

• 发表时间: 2006
• 期刊: Clinical Rheumatology 18(4)
• 作者: Moriyama M;Hayashi N;Ohyabu C;Muikai M;Kawano S;Kumagai S.;Masahiro Koshiba
• 通讯作者: Masahiro Koshiba

Thioredoxin protects against joint destruction in a murine arthritis model.

• DOI: 10.1016/j.freeradbiomed.2006.01.006
• 发表时间: 2006-05
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: G. Tsuji;M. Koshiba;Hajime Nakamura;Hidekazu Kosaka;S. Hatachi;Chiyo Kurimoto;M. Kurosaka;Y. Hayashi;J. Yodoi;S. Kumagai

関節リウマチ(RA)におけるアデノシンデアミナーゼ過剰発現とその病的意義

类风湿性关节炎（RA）中腺苷脱氨酶的过度表达及其病理意义

• 发表时间: 2005
• 期刊: 臨床病理 53・8
• 作者: Hatakenaka M;et al.;長谷川 均 他。;Kobayashi M;小柴 賢洋
• 通讯作者: 小柴 賢洋