Localisation of apoptosis and expression of apoptosis related proteins in the synovium of patients with rheumatoid arthritis.

Abstract

Objectives-To investigate whether apoptosis occurs in the synovium of rheumatoid arthritis (RA), and the intermediate molecules operating in this process. Methods-DNA fragmentation was detected by in situ nick end labelling (ISNEL) in the synovium ofpatients with RA (n = 11) and control patients with femoral neck fracture (n = 5). The expression of proteins p53, p21WAF1/CIP1, c-myc, proliferating cell nuclear antigen (PCNA), and Bcl-2 was also examined by immunohistochemistry. Results-ISNEL positive synovial cells with apoptosis specific morphology were detected in extremely limited areas in only two RA synovial tissue specimens. Proteins p53, p2lWAFl'cPl, and c-myc, known inducers ofapoptosis or cell cycle arrest or both, were expressed in the sublining cells independent of ISNEL positive cells. PCNA, a marker for cell proliferation, was observed in the synovial lining cells. Bcl-2, an inhibitor of apoptosis, was expressed mainly in infiltrated lymphocytes and in parts of the sublining layer cells of RA; it also did not correspond with ISNEL staining. Conclusions-Our findings indicate that RA synovial cells undergo apoptosis in addition to cell proliferation, but the frequency of apoptosis was very low. We suspect that the apoptotic process in the RA synovium may be suppressed by overexpression of Bcl-2. Although expressed proteins p53, p21WAFl'CIP1, and c-myc were present in the RA synovium, these protooncogenes are probably not implicated in the apoptotic process. (Ann Rheum Dis 1996; 55: 442-449) Apoptosis, or programmed cell death, is a fundamental process that occurs during morphogenesis and development of the immune system.' 2 Although the mechanism of apoptosis is still unclear, the process proceeds through the activation of an intrinsic cell suicide programme and exhibits specific morphology distinct from that associated with accidental cell death. However, synovial cell death does seem to occur during the natural history of RA, counteracting cell proliferation: the synovial fluid often contains rice bodies, which are thought to be derived from the synovial tissue as a result of cell death." 12 Moreover, during the late stage of the disease, the proliferated synovial tissue is replaced by connective tissue.'3 This suggests that apoptosis may also be involved in synovial cell death and in preventing the development of malignancy despite the neoplastic behaviour of synovial cells.To investigate whether apoptosis occurs in the synovium of RA, we studied DNA fragmentation by the in situ nick end labelling (ISNEL) method. We also used immunohistochemical techniques to examine proteins related to apoptosis or cell cycle arrest to investigate the state of synovial cells with respect to apoptosis. Patients and methods PATIENTS AND TISSUESInformed consent was obtained from each patient. Synovial tissue samples were obtained from 11 patients with RA at the time of joint replacement surgery of the hip or knee, or synovectomy of the wrist ( The overall degree of lymphocyte infiltration was assessed as ...

Bcl-2 Expression in Synovial Fibroblasts Is Essential for Maintaining Mitochondrial Homeostasis and Cell Viability

“…Here, we demonstrated by immunohistochemistry that Bcl-2 was highly expressed in RA compared with OA ST. Dual immunofluorescence showed that although macrophages were variably positive, the majority of the Bcl-2-positive cells in the synovial lining and the sublining region were CD68-negative, synovial fibroblasts. In contrast, other studies revealed little Bcl-2 expression in the synovial lining (38) or sublining (40). The observed differences between these investigations and ours may have been technical.…”

Cooperation of Ras‐ and c‐Myc–dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis

“…So far, the question of whether alterations in the expression of c-Myc contribute specifically to the activation and invasiveness of RASFs (5) has not been investigated. Instead, there have been conflicting data, some of which have suggested a contribution of c-Myc to synovial proliferation (30), while others have pointed to apoptosis (51) or indicated no specific role of c-Myc in RA (52,53). Although c-myc mRNA does not appear to be increased in RASFs, c-Myc protein has been detected at sites of destruction (40).…”

Mcl-1 Is Essential for the Survival of Synovial Fibroblasts in Rheumatoid Arthritis

“…The mechanisms that contribute to the persistence of chronic inflammation observed in RA are poorly characterized; however, regulation of the proliferation of synovial fibroblasts and their resistance to apoptosis may be crucial in the pathogenesis of this disease (2). Histological evidence of apoptosis has not been observed in RA synovial tissue examined by electron microscopy (3,4). Joint inflammation and destruction in a variety of animal models, including streptococcal cell wall-induced arthritis, collagen-induced arthritis, the human T cell leukemia virus 1 tax transgenic model, and RA explants in SCID mice, have each been ameliorated by enhanced apoptosis (5)(6)(7), suggesting that increased apoptosis may be associated with an improved clinical outcome.…”