Intercellular adhesion molecule 1 underlies the functional heterogeneity of synovial cells in patients with rheumatoid arthritis: Involvement of cell cycle machinery

Abstract

Objective. To investigate whether synovial cells from rheumatoid arthritis (RA) synovium can be divided into 2 functionally different subpopulations: active or proliferative cells and apoptotic cells. Methods. Expression of cell surface and cyto-plasmic molecules on synovial cells was assessed by immunohistochemistry, flow cytometry, or Western blotting. Cells were categorized as intercellular adhesion molecule 1 (ICAM-1) positive or negative based on positive and negative selection of antibody-coated beads. Cell cycle and apoptosis were assessed using propidium iodide staining, TUNEL method, and DNA fragmentation. Results. Expression of ICAM-1 and Fas was noted mainly in the synovial lining to sublining layer in vivo, and synovial cells could be clearly distinguished as ICAM-1 positive or negative. The expression of Fas was higher on ICAM-1-positive cells than on ICAM-1-negative cells in vitro. The functional and phenotypic heterogeneity between ICAM-1-positive and-negative cells was further emphasized by cell cycle machinery. The majority of ICAM-1-positive cells were arrested at the G0/G1 phase, whereas many of the ICAM-1-negative cells were at the S to G2/M proliferating phase. In ICAM-1-positive cells, p53 and p21 expression was up-regulated and cyclin-dependent protein kinase 6 activity was inhibited. Most ICAM-1-positive cells were apoptotic (as evidenced by TUNEL positivity and DNA fragmentation). ICAM-1-positive cells were induced not only by interleukin-1, but also by Fas crosslinking. Conclusion. ICAM-1-positive synovial cells represent growth arrest and subsequent apoptosis, whereas ICAM-1-negative cells are proliferative. Such differences in regulation of the cell cycle based on ICAM-1 status are important determinants of the lifespan, proliferation , and growth arrest of RA synoviocytes.

Taurine chloramine inhibits proliferation of rheumatoid arthritis synoviocytes by triggering a p53-dependent pathway

“…Accumulating evidence from in vitro and in vivo studies suggests that p53-dependent pathway plays an adaptive role in FLS by keeping them in the quiescent state. For example, synovial lining cells and cultured RA FLS that are in the G0/G1 state show characteristic up-regulated expression of p53) [5,6] (see also Discussion).…”

“…The expression of p27 mRNA is constant throughout the cell cycle, and p27 availability is regulated mostly at the protein level by translational control and ubiquitin-mediated proteolysis [16]. Interestingly, p21 and p27 seem to participate in the maintenance of RA FLS in quiescent G0/G1 state both in synovial tissue and in culture conditions [5,6]. Opposite to CDKIs, proliferating cell nuclear antigen (PCNA) and survivin are positive regulators of the cell cycle progression and the expression of these proteins is highly elevated in proliferating cells [17,18].…”

A Question of Transformation

“…9,10 Discrepancies in these studies might be the result of differences in the stage of synovial tissue used for isolation of synoviocytes, the type of synoviocytes, or culture conditions. 11,12 Defective apoptosis is a second mechanism contributing to synovial hyperplasia. Whereas initial studies indicated increased levels of apoptosis in the rheumatoid synovium, recent investigations have demonstrated both in vivo and in vitro evidence of the resistance of synoviocytes to apoptosis.…”

β1 integrin–mediated signaling induces intercellular adhesion molecule 1 and Fas on rheumatoid synovial cells and Fas‐mediated apoptosis

“…We previously reported that ICAM‐1–positive RA synovial cells, which also express Fas, undergo growth arrest and subsequent apoptosis, whereas ICAM‐1–negative cells are proliferative (8). However, little is known about the mechanism of induction of these apoptotic synovial cells.…”