The functional heterogeneity of synovial cells in patients with rheumatoid arthritis.

类风湿关节炎患者滑膜细胞的功能异质性。

基本信息

批准号：
11670469
负责人：
TANAKA Yoshiya
金额：
$ 2.3万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670469/
关键词：
Rheumatoid arthritis synovial cells adhesion molecules ICAM-1 hyaluronan CD44 cell cycle apoptosis Fas T細胞サイトカイン細胞死細胞増殖

项目摘要

Rheumatoid arthritis (RA) are characterized by synovial proliferation and accumulation of inflammatory cells. Hyperactivation of synovial cells leads to hyperplasia of the synovial membrane and production of inflammatory cytokines and degradative enzymes that result in further destruction of cartilage and bone. However, accumulating evidence indicates that spontaneous growth arrest and remission are observed in RA synovial cells. Such paradoxical phenomena of RA synovial cells ; activation/proliferation and cell cycle arrest/apoptosis, prompted us to investigate whether synovial cells can be classified into functionally different subpopulations. The concept of differential regulation of certain adhesion molecules on different cell subsets and their relevance to cellular functions is emerging. We here document that ICAM-1-positive synovial cells prepared from patients with RA show high Fas expression, growth arrest and subsequent apoptosis, whereas ICAM-1-negative cells are highly proliferative. The distinctive regulation of cell cycle based on ICAM-1 expression is an important determinant of the life span of synovial cells where paradoxical phenomena of hyper-proliferation and growth arrest are observed. Here we also propose a novel function for CD44, known as a hyaluronan receptor, using synovial cells. The results indicate that CD44 is deeply concerned in Fas expression and that CD44 further augments Fas/Fas-L-mediated apoptosis of synovial cells by augmenting the adhesion of synovial cells with T cells through up-regulation of VCAM-1 on synovial cells. Thus, our results suggest that inhibition of synovial cell proliferation could be achieved by targeting ICAM-1-negative cells and that the rational design of future therapeutic strategies for RA synovitis may thereby include the exploitation of CD44 and Fas death pathway in order to directly reduce growth of synovial cells in vivo.

类风湿关节炎（RA）的特征是滑膜增殖和炎症细胞的积累。滑膜细胞的过度激活导致滑膜的增生以及炎症细胞因子和降解酶的产生，从而导致软骨和骨骼进一步破坏。但是，积累的证据表明在RA滑膜细胞中观察到自发生长停滞和缓解。这种RA滑膜细胞的这种矛盾现象；激活/增殖和细胞周期停滞/凋亡，促使我们研究了滑膜细胞是否可以分为功能不同的亚群。某些粘附分子在不同细胞子集上的差异调节概念及其与细胞功能的相关性正在出现。我们在这里记录，由RA患者制备的ICAM-1阳性滑膜细胞表现出高FAS表达，生长停滞和随后的凋亡，而ICAM-1阴性细胞具有很高的增殖。基于ICAM-1表达的细胞周期的独特调节是滑膜细胞寿命的重要决定因素，在观察到超增殖和生长停滞的悖论现象。在这里，我们还提出了使用滑膜细胞的CD44（称为透明质酸受体）的新功能。结果表明，CD44深深关注FAS的表达，CD44通过通过上调通过分层细胞上的上调来增强滑细胞与T细胞的粘附在滑细胞上的粘附，从而进一步增强了滑膜细胞的FAS/FAS-L介导的细胞凋亡。因此，我们的结果表明，可以通过靶向ICAM-1阴性细胞来抑制滑膜细胞增殖，并且可以将未来的RA滑膜炎治疗策略理性设计包括在内，从而包括对CD44和FAS死亡途径的开发，以直接降低。滑膜在体内的生长。