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

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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.