Small ubiquitin-like modifier 1 [corrected] mediates the resistance of prosthesis-loosening fibroblast-like synoviocytes against Fas-induced apoptosis.
OBJECTIVE
To study the expression of small ubiquitin-like modifier 1 (SUMO-1) in aseptic loosening of prosthesis implants and to investigate its role in regulating the susceptibility of prosthesis-loosening fibroblast-like synoviocytes (FLS) to Fas-induced apoptosis.


METHODS
Specimens of aseptically loosened tissue were obtained at revision surgery, and the expression of SUMO-1 was analyzed by in situ hybridization. SUMO-1 levels in FLS were determined by quantitative polymerase chain reaction and Western blot analysis. Immunohistochemistry and confocal microscopy were used to study the subcellular localization of SUMO-1. The functional role of SUMO-1 in Fas-induced apoptosis of prosthesis-loosening FLS was investigated by small interfering RNA-mediated knockdown of SUMO-1 and by gene transfer of the nuclear SUMO-specific protease SENP1.


RESULTS
SUMO-1 was expressed strongly in aseptically loosened tissue and was found prominently at sites adjacent to bone. Prosthesis-loosening FLS expressed levels of SUMO-1 similar to the levels expressed by rheumatoid arthritis (RA) FLS, with SUMO-1 being found mainly in promyelocytic leukemia protein nuclear bodies. Knockdown of SUMO-1 had no effect on spontaneous apoptosis but significantly increased the susceptibility of prosthesis-loosening FLS to Fas-induced apoptosis. Gene transfer of the nuclear SUMO-specific protease SENP1 reverted the apoptosis-inhibiting effects of SUMO-1.


CONCLUSIONS
These data suggest that SUMO-1 is involved in the activation of both RA FLS and prosthesis-loosening FLS by preventing these cells from undergoing apoptosis. Modification of nuclear proteins by SUMO-1 contributes to the antiapoptotic effects of SUMO-1 in prosthesis-loosening FLS, providing evidence for the specific activation of sumoylation during their differentiation. Therefore, SUMO-1 may be an interesting target for novel strategies to prevent aseptic prosthesis loosening.
Meinecke
Ingmar
I
University Hospital Muenster, Muenster, Germany.
Pap
Géza
G
Mendoza
Heidi
H
Drange
Steffen
S
Ender
Stephan
S
Strietholt
Simon
S
Gay
Renate E
RE
Seyfert
Christine
C
Ink
Barbara
B
Gay
Steffen
S
Pap
Thomas
T
Peters
Marvin A
MA
D017209:Apoptosis / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006621:Hip Joint / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology; D011475:Prosthesis Failure; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D025842:SUMO-1 Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology*; D019014:fas Receptor / Q000378:metabolism*
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; D019014:fas Receptor; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases