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.
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Authors | Ingmar Meinecke, Géza Pap, Heidi Mendoza, Steffen Drange, Stephan Ender, Simon Strietholt, Renate E Gay, Christine Seyfert, Barbara Ink, Steffen Gay, Thomas Pap, Marvin A Peters |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 60
Issue 7
Pg. 2065-70
(Jul 2009)
ISSN: 0004-3591 [Print] United States |
PMID | 19565496
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- RNA, Messenger
- RNA, Small Interfering
- SUMO-1 Protein
- fas Receptor
- Endopeptidases
- SENP1 protein, human
- Cysteine Endopeptidases
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Topics |
- Apoptosis
(physiology)
- Arthritis, Rheumatoid
(metabolism, pathology)
- Cysteine Endopeptidases
- Endopeptidases
(genetics, metabolism)
- Gene Knockdown Techniques
- Hip Joint
(metabolism, pathology)
- Humans
- Knee Joint
(metabolism, pathology)
- Prosthesis Failure
- RNA, Messenger
(metabolism)
- RNA, Small Interfering
(pharmacology)
- SUMO-1 Protein
(drug effects, genetics, metabolism)
- Synovial Membrane
(metabolism, pathology)
- fas Receptor
(metabolism)
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