Key result
Fas ligation induced apoptosis in rheumatoid arthritis synoviocytes via activation of the FADD/caspase-8/caspase-3 signaling pathway, which was suppressed by caspase-3 and -8 specific inhibitors.
Fas-mediated apoptosis in RA synoviocytes is regulated by FADD recruitment to the DISC and subsequent activation of the caspase-8/caspase-3 signaling pathway.
Supports Fas-mediated apoptosis targeting in RA; leaves open translation to human disease or CV comorbidities.
OBJECTIVE: To understand the intracellular regulatory mechanisms in Fas-mediated apoptosis of synoviocytes, we examined the involvement of caspases [caspase-1/ICE (interleukin-1beta converting enzyme), caspase-3/CPP32, and caspase-8/FLICE] and Fas-associated death domain protein (FADD) forming a death-inducing signalling complex (DISC) in Fas-mediated apoptosis of synoviocytes. METHODS: Synoviocytes were obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. The number of dead cells was counted after treatment with anti-Fas monoclonal antibody in the presence of caspase-1-, -3-, or -8-specific inhibitors. The involvement of caspases and FADD in Fas-mediated apoptosis of RA synoviocytes was examined by immunoblot and immunoprecipitation analyses. RESULTS: RA synoviocytes expressed high levels of caspase-3, caspase-8, and FADD compared with OA synoviocytes. Interestingly, Fas ligation activated caspase-8 and caspase-3 with the cleavage of poly(ADP-ribose) polymerase (PARP), corresponding to apoptosis of RA synoviocytes. Furthermore, specific inhibitors for caspase-3 and caspase-8 but not caspase-1 suppressed Fas-induced apoptosis of RA synoviocytes in a dose- and time-dependent manner. Caspase-8-specific inhibitor suppressed the activation of caspase-3 after Fas ligation on RA synoviocytes. Importantly, FADD was selectively recruited to the Fas death domain during Fas-mediated apoptosis of RA synoviocytes, consistent with sensitivity to the Fas-mediated apoptosis. CONCLUSION: Our findings suggest that Fas-mediated apoptosis in synoviocytes may be regulated at the level of recruitment of FADD to the DISC, subsequently leading to the activation of the FADD/caspase-8/caspase-3 signalling pathway.
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Okamoto et al. (2000) studied Rheumatoid arthritis and osteoarthritis. Anti-Fas monoclonal antibody with caspase-specific inhibitors vs. Osteoarthritis synoviocytes / absence of inhibitors was evaluated on Fas-mediated apoptosis and caspase activation. Fas ligation induced apoptosis in rheumatoid arthritis synoviocytes via activation of the FADD/caspase-8/caspase-3 signaling pathway, which was suppressed by caspase-3 and -8 specific inhibitors.
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