Analysis of pathogenesis and control of arthritis in rheumatoid arthritis by calpain-calpastatin system

钙蛋白酶-钙蛋白酶抑制素系统分析类风湿性关节炎发病机制及防治

• 批准号: 16390287
• 负责人: MIMORI Tsuneyo
• 金额: $ 9.22万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390287/
• 关键词: calpastatin; calpain; calpain inhibitor; rheumatoid arthritis; IL-6; autoantibody; Th1; Th2 balance; synoviocyte; T細胞; IL-1; マウス関節炎モデル

We have previously reported that one of target autoantigens recognized by autoantibodies in rheumatoid arthritis (RA) patients is calpastatin, an endogenous inhibitor of calcium-dependent cysteine proteinase (calpain), and that IgG fraction of RA patient sera inhibits the function of calpastatin and increases the proteolytic activity of calpain. Calpain is thought to be a neutral proteinase that regulates activation of various inflammation factors and may be involved in cartilage degradation. Our study aims to investigate the pathogenesis and new therapeutic strategy of RA by calpain-calpastatin system.1.Amelioration of mouse model arthritis by calpain inhibitorMonoclonal anti-type II collagen antibodies-induced arthritis in Balb/c mice was significantly inhibited by intraperitoneal injection of calpain inhibitor E-64-d. Quantitative RT-PCR demonstrated that mRNA levels of IL-1 and IL-6 were significantly suppressed in the joint tissues of E-64-d-treated mice. Production of IL-6 and IL-1 was also suppressed in dose-dependent manner in cultured synoviocytes from RA patients when E-64-d was added.2.Effect of over expression of calpastatin in activation of fibroblasts and T cellsNatural expression of calpastatin was significantly decreased in Th1 cells, especially in activated Th1 cells, than in Th2 cells. When splenic CD4+T cells from Balb/c mice and 3T3 fibroblasts were transfected by human calpastatin cDNA-recombinant retrovirus vector, production of IL-6 and interferon-γ was significantly suppressed.Thus, in RA patients, increased calpain activity may be involved in exacerbation of arthritis by differentiating CD4+T cells from Th2 to Th1, as well as over production of IL-6 in synovial cells.

我们先前报道，类风湿关节炎(RA)患者自身抗体识别的靶抗原之一是钙化半胱氨酸蛋白酶(Calain)的内源性抑制物calastatin，而RA患者血清中的免疫球蛋白组份抑制calastatin的功能并增强calain的蛋白分解活性。钙蛋白酶被认为是一种中性蛋白酶，调节各种炎症因子的激活，可能参与软骨的降解。本研究旨在探讨Calain-calastatin系统治疗类风湿关节炎的机制及新的治疗策略。1.Calain抑制剂对小鼠关节炎模型的改善作用Calain抑制剂E--d可显著抑制抗II型胶原抗体诱导的小鼠关节炎。定量RT-PCR结果显示，E--d组小鼠关节组织中IL-1和IL-6mRNA的表达水平明显受到抑制。加入E--d后，RA患者滑膜细胞中IL-6和IL-1的产生也受到抑制，且呈剂量依赖关系。2.Calastatin过表达对成纤维细胞和T细胞的激活作用Th1细胞，尤其是活化的Th1细胞，其自然表达明显低于Th2细胞。重组逆转录病毒载体转染BALB/c小鼠和3T3成纤维细胞后，IL-6和干扰素-γ的产生受到明显抑制，提示类风湿关节炎患者可能通过向Th2和Th1细胞分化而增加Calain活性，并在滑膜细胞中过度产生IL-6。

项目成果

Clinical significance of anti-CCP antibodies in rheumatoid arthritis.

• DOI: 10.2169/internalmedicine.44.1122
• 发表时间: 2005-11
• 期刊: Internal medicine
• 影响因子: 1.2
• 作者: T. Mimori

Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in a mouse model of arthritis

• DOI: 10.1002/art.20023
• 发表时间: 2004-02-01
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Kawabata, D;Tanaka, M;Ozaki, S
• 通讯作者: Ozaki, S

関節リウマチ早期診断と抗CCP抗体

类风湿性关节炎的早期诊断和抗CCP抗体

• 发表时间: 2005
• 期刊: リウマチ科 34(3)
• 作者: Ichikawa Y;Mimori T;et al.;三森経世
• 通讯作者: 三森経世

Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis.

• DOI: 10.1084/jem.20041685
• 发表时间: 2005-07-18
• 期刊: The Journal of experimental medicine
• 作者: Miyaji M;Jin ZX;Yamaoka S;Amakawa R;Fukuhara S;Sato SB;Kobayashi T;Domae N;Mimori T;Bloom ET;Okazaki T;Umehara H
• 通讯作者: Umehara H

Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis

• DOI: 10.1002/art.21023
• 发表时间: 2005-05-01
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Sato, S;Hirakata, M;Ikeda, Y
• 通讯作者: Ikeda, Y