Development of the novel therapeutic method for rheumatoid arthritis based on the redox regulation

基于氧化还原调节的类风湿关节炎新治疗方法的开发

基本信息

批准号：
15591054
负责人：
KOSHIBA Masahiro
金额：
$ 2.24万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

1.Anti-arthritis effects of thioredoxin (TRX) transgenic mice (TRX-Tg)Since TRX-Tg have C57BL/6 background and are resistant to collagen-induced arthritis, arthritis was induced by the intraperitoneal injection of anti-collagen type II monoclonal antibody cocktail.(1)Arthritis was 100% induced at day 6 on wild-type mice (Wt) while only few TRX-Tg developed arthritis on day 7, thus the late onset of arthritis was observed.(2)On Wt, joint redness and swelling were significant and the joint scores were 7 to 14 (average 10). On TRX-Tg only slight, if any, joint redness and swelling were observed and the joint scores were 0 (no arthritis) to 2.(3)Histologically synovial proliferation, neutrophil infiltration and cartilage destruction were mild in TRX-Tg compared to Wt. Inhibition of cartilage apoptosis was proved.2.Anti-arthritis effects of exogenous TRXArthritis was induced in the same manner on Wt and recombinant TRX (rTRX) was injected intraperitoneally every day. Onset of arthritis was similarly delayed one day by rTRX administration. Inhibition of joint swelling was also achieved by rTRX administration but not as strong as was observed on TRX-Tg.These results indicate that the inhibition of oxidative stress by enough amount of TRX may lead to the novel therapeutic method for rheumatoid arthritis (RA).3.The effect of adenosine on TRX expression of synoviocytesTo investigate if the anti-oxidative function of adenosine, the effector molecule of anti-rheumatic effects of methotrexate, is related to the TRX, synoviocytes from RA patients were incubated with adenosine and the change of TRX expression was estimated by ELISA and flow cytometry. Adenosine had no influence to the TRX levels, which suggests that anti-rheumatic effects of adenosine may not be at least directly related to the TRX.

1.硫氧还蛋白（TRX）转基因小鼠（TRX-Tg）的抗关节炎作用由于TRX-Tg具有C57BL/6背景并且对胶原诱导的关节炎具有抵抗力，因此通过腹腔注射抗II型胶原单克隆抗体诱导关节炎(1)野生型小鼠 (Wt) 在第 6 天 100% 诱导关节炎，而当天只有少数 TRX-Tg 出现关节炎(2)Wt时关节红肿明显，关节评分为7～14分(平均10分)。在TRX-Tg上仅观察到轻微的（如果有的话）关节发红和肿胀，并且关节评分为0（无关节炎）至2。（3）与Wt相比，TRX-Tg的组织学滑膜增殖、中性粒细胞浸润和软骨破坏是轻微的。证实了对软骨细胞凋亡的抑制作用。2.外源性TRX的抗关节炎作用Wt以同样的方式诱导关节炎，每天腹腔注射重组TRX(rTRX)。 rTRX 给药同样将关节炎的发作延迟了一天。 rTRX 给药也能抑制关节肿胀，但不如 TRX-Tg 上观察到的那么强。这些结果表明，足够量的 TRX 抑制氧化应激可能会导致类风湿性关节炎 (RA) 的新治疗方法。 3.腺苷对滑膜细胞TRX表达的影响探讨甲氨蝶呤抗风湿作用的效应分子腺苷的抗氧化功能是否与滑膜细胞TRX表达有关。 TRX，将RA患者的滑膜细胞与腺苷一起孵育，并通过ELISA和流式细胞术评估TRX表达的变化。腺苷对 TRX 水平没有影响，这表明腺苷的抗风湿作用可能至少与 TRX 没有直接关系。