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 interact with the signal-competent form of Fas/APO-1 and tumor necrosis factor receptor I (TNFRI), and thereby, to protect cells against anti-Fas/APO-1- and 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 synovium from patients with RA.


METHODS
The expression of sentrin-1 mRNA was examined by in situ hybridization on snap-frozen sections of normal and RA synovial tissues as well as on paraffin-embedded RA synovial specimens, including the interface of cartilage-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 expression in RA synovial fibroblasts (RASF), osteoarthritis synovial fibroblasts (OASF), and normal fibroblasts was performed by quantitative real-time polymerase chain reaction. Expression levels were standardized to the expression of GAPDH. The in vivo maintenance of sentrin expression in RASF aggressively invading human cartilage was explored in the SCID mouse model of RA.


RESULTS
A marked expression of sentrin-1 mRNA could be seen in all RA synovial specimens, predominantly in SF of the lining layer and at sites of invasion of RA synovium into cartilage. In normal synovial tissues, no sentrin-1 mRNA was detectable. RASF showed a maximum 32.5-fold (mean +/- SD 14.9 +/- 11.6) increase of sentrin-1 mRNA expression compared with normal fibroblasts 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 model, invading RASF maintained their sentrin-1 mRNA expression for at least 60 days in vivo.


CONCLUSIONS
The marked expression of sentrin in rheumatoid 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 thereby extend the lifespan of invasive, cartilage-destructive SF.
Franz
J K
JK
University Hospital, Zürich, Switzerland.
Pap
T
T
Hummel
K M
KM
Nawrath
M
M
Aicher
W K
WK
Shigeyama
Y
Y
Müller-Ladner
U
U
Gay
R E
RE
Gay
S
S
D000818:Animals; D000918:Antibody Specificity; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D025842:SUMO-1 Protein; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D014452:Ubiquitins / Q000096:biosynthesis* / Q000235:genetics
D019394:Ki-67 Antigen; D012333:RNA, Messenger; D025842:SUMO-1 Protein; D014452:Ubiquitins