Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts.
OBJECTIVE
There is evidence that proliferation of synovial fibroblasts 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 ultrastructural 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 characteristics 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 were in different stages of apoptosis. In OA, no apoptotic cells could be observed. Apoptosis of synovial fibroblasts in RA showed a characteristic multistage pattern. In each of the distinguishable 4 stages, specific 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 expression was limited to the first stage of apoptosis. Conversely, the synovial fibroblasts located in the synovial lining layer neither underwent apoptosis nor expressed Fas antigen. Several synovial lining cells expressed the cell death suppressor (anti-apoptosis) gene product Bcl-2.


CONCLUSIONS
Apoptosis of fibroblasts in the RA synovial sublining is characterized by a distinct multistep ultrastructural pattern with a detectable initial Fas antigen expression; conversely, reduced apoptosis in the synovial lining associated with the expression of Bcl-2 results in extended life of matrix degrading synovial fibroblasts at the site of synovial invasion into cartilage and bone.
Matsumoto
S
S
Department of Medicine, University of Alabama at Birmingham, USA.
Müller-Ladner
U
U
Gay
R E
RE
Nishioka
K
K
Gay
S
S
D000328:Adult; D000368:Aged; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D010003:Osteoarthritis / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure*; D019014:fas Receptor / Q000032:analysis*
D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor