权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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)以滑膜增殖和炎性细胞聚集为特征。滑膜细胞的过度激活导致滑膜的增殖，产生炎性细胞因子和降解酶，导致软骨和骨骼的进一步破坏。然而，越来越多的证据表明，在RA滑膜细胞中可观察到自发生长停滞和缓解。RA滑膜细胞的这种自相矛盾的现象：激活/增殖和细胞周期停滞/凋亡，促使我们研究滑膜细胞是否可以分为功能不同的亚群。某些黏附分子在不同细胞亚群上的不同调节及其与细胞功能的相关性的概念正在出现。我们发现，从RA患者制备的ICAM-1阳性的滑膜细胞表现出高Fas表达、生长停滞和随后的凋亡，而ICAM-1阴性的细胞则高度增殖。基于ICAM-1表达对细胞周期的独特调控是滑膜细胞寿命的重要决定因素，在滑膜细胞中观察到过度增殖和生长停滞的矛盾现象。在这里，我们还提出了CD44的一种新功能，称为透明质酸受体，使用滑膜细胞。结果表明，CD44与Fas的表达密切相关，CD44通过上调滑膜细胞表面血管细胞黏附分子-1的表达，增强滑膜细胞与T细胞的黏附，进一步增强Fas/Fas-L介导的滑膜细胞凋亡。因此，我们的结果提示，可以通过靶向ICAM-1阴性的细胞来抑制滑膜细胞的增殖，从而合理地设计未来RA滑膜炎的治疗策略，从而可能包括开发CD44和Fas死亡通路，以直接减少体内滑膜细胞的生长。