ULTRASTRUCTURAL DEMONSTRATION OF APOPTOSIS, FAS AND BCL-2 EXPRESSION OF RHEUMATOID SYNOVIAL FIBROBLASTS

Objective, There is evidence that proliferation of synovial fibroblast s and invasive growth in rheumatoid arthritis (RA) is due to impaired regulation of the cell cycle, i.e., the balance between proliferation and physiological cell death (apoptosis). We examined synovial tissues from patients with RA and osteoarthritis (OA) to determine the ultras tructural changes during apoptosis and the expression of the apoptosis regulating molecules Fas and Bcl-2 in synovial fibroblasts. Methods. We examined synovial tissues obtained from patients with RA and OA by electron microscopy and immunoelectron microscopy to evaluate the char acteristics of apoptosis in RA synovial fibroblasts as well as Fas and Bcl-2 antigen expression. Results. Ultrastructurally, the majority of the RA synovial fibroblasts appeared transformed, and 3% of these wer e in different stages of apoptosis, In OA, no apoptotic cells could be observed. Apoptosis of synovial fibroblasts in RA showed a characteri stic multistage pattern. In each of the distinguishable 4 stages, spec ific ultrastructural changes could be detected. The apoptotic synovial fibroblasts were mainly located in the deeper sublining layers of the synovium. Immunoelectron microscopy revealed that Fas antigen express ion was limited to the first stage of apoptosis. Conversely, the synov ial fibroblasts located in the synovial lining layer neither underwent apoptosis nor expressed Fas antigen, Several synovial lining cells ex pressed the cell death suppressor (anti-apoptosis) gene product Bcl-2. Conclusion. Apoptosis of fibroblasts in the RA synovial sublining is characterized by a distinct multistep ultrastructural pattern with a d etectable initial Fas antigen expression; conversely, reduced apoptosi s in the synovial lining associated with the expression of Bcl-2 resul ts in extended life of matrix degrading synovial fibroblasts at the si te of synovial invasion into cartilage and bone.