Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis

Objective. Sentrin, a novel antiapoptotic molecule, has been shown to inter act with the signal-competent form of Fas/APO-1 and tumor necrosis factor r eceptor I (TNFRI), and thereby, to protect cells against anti-Fas/APO-1- an d TNF-induced cell death, Since reduced apoptosis in the synovial lining is supposed to contribute to synovial hyperplasia in rheumatoid arthritis (RA ), we searched for the expression of sentrin-1 messenger RNA (mRNA) in syno vium from patients with RA. Methods. The expression of sentrin-1 mRNA was examined by in situ hybridiza tion on snap-frozen sections of normal and RA synovial tissues as well as o n paraffin-embedded RA synovial specimens, including the interface of carti lage-bone and invading synovium, Immunohistochemical double labeling after in situ hybridization was performed to further characterize sentrin-1 mRNA- expressing cells. In addition, quantitative analysis of sentrin-1 mRNA expr ession in RA synovial fibroblasts (RASF), osteoarthritis synovial fibroblas ts (OASF),and normal fibroblasts was performed by quantitative real-time po lymerase chain reaction. Expression levels were standardized to the express ion of GAPDH, The in vivo maintenance of sentrin expression in EASE aggress ively invading hu-man cartilage was explored in the SCID mouse model of RA. Results, A marked expression of sentrin-1 mRNA could be seen in all RA syno vial specimens, predominantly in SF of the lining layer and at sites of inv asion of RA synovium into cartilage. In normal synovial tissues, no sentrin -l mRNA was detectable. EASE showed a maximum 32.5-fold (mean +/- SD 14.9 /- 11.6) increase of sentrin-l mRNA expression compared with normal fibrobl asts and a maximum 31.4-fold (mean +/- SD 14.3 +/- 10.9) increase compared with OASF, When coimplanted with normal human cartilage in the SCID mouse m odel, invading RASF maintained their sentrin-l mRNA expression for at least 60 days in vivo. Conclusion. The marked expression of sentrin in rheumatoi d synovial tissue, but not in normal or OA synovial tissue, may contribute to the modulation of Fas- and TNFR-mediated apoptosis in RA synovium, and t hereby extend the lifespan of invasive, cartilage-destructive SF.