1. Small ubiquitin-like modifier 1 [corrected] mediates the resistance of prosthesis-loosening fibroblast-like synoviocytes against Fas-induced apoptosis.
- Author
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Meinecke I, Pap G, Mendoza H, Drange S, Ender S, Strietholt S, Gay RE, Seyfert C, Ink B, Gay S, Pap T, and Peters MA
- Subjects
- Arthritis, Rheumatoid metabolism, Arthritis, Rheumatoid pathology, Cysteine Endopeptidases, Endopeptidases genetics, Endopeptidases metabolism, Gene Knockdown Techniques, Hip Joint metabolism, Hip Joint pathology, Humans, Knee Joint metabolism, Knee Joint pathology, RNA, Messenger metabolism, RNA, Small Interfering pharmacology, SUMO-1 Protein drug effects, SUMO-1 Protein genetics, Apoptosis physiology, Prosthesis Failure, SUMO-1 Protein metabolism, Synovial Membrane metabolism, Synovial Membrane pathology, fas Receptor metabolism
- Abstract
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., Conclusion: 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.
- Published
- 2009
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