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Small ubiquitin-like modifier 1 [corrected] mediates the resistance of prosthesis-loosening fibroblast-like synoviocytes against Fas-induced apoptosis.

AbstractOBJECTIVE:
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.
AuthorsIngmar 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
JournalArthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 7 Pg. 2065-70 (Jul 2009) ISSN: 0004-3591 [Print] United States
PMID19565496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • RNA, Messenger
  • RNA, Small Interfering
  • SUMO-1 Protein
  • fas Receptor
  • Endopeptidases
  • SENP1 protein, human
  • Cysteine Endopeptidases
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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