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

类风湿关节炎（RA）的特点是滑膜增生和炎症细胞的积累。滑膜细胞的过度活化导致滑膜增生，产生炎性细胞因子和降解酶，从而进一步破坏软骨和骨骼。然而，越来越多的证据表明，在RA滑膜细胞中观察到自发生长停止和缓解。类风湿性关节炎滑膜细胞的矛盾现象；激活/增殖和细胞周期阻滞/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。某些粘附分子对不同细胞亚群的差异调节及其与细胞功能的相关性的概念正在出现。我们在此证明，从RA患者制备的icam -1阳性滑膜细胞显示高Fas表达，生长停滞和随后的凋亡，而icam -1阴性细胞具有高度增殖。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，滑膜细胞可以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，利用滑膜细胞。结果表明，CD44与Fas的表达密切相关，CD44通过上调滑膜细胞上的VCAM-1，增强滑膜细胞与T细胞的粘附，从而进一步增强Fas/Fas- l介导的滑膜细胞凋亡。因此，我们的研究结果表明，可以通过靶向icam -1阴性细胞来抑制滑膜细胞的增殖，从而合理设计RA滑膜炎的未来治疗策略可能包括利用CD44和Fas死亡途径，以直接减少体内滑膜细胞的生长。

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.