| 75kDa SirT1 blocks TNFα-mediated apoptosis in human osteoarthritic chondrocytes. | |
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MedLine Citation:
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PMID: 21987377 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVE: SirT1 has been previously implicated in the regulation of human cartilage homeostasis and chondrocyte survival. Exposing human osteoarthritic chondrocytes to TNFα generates a stable and enzymatically inactive 75kDa form of SirT1 (75SirT1) via Cathepsin B-mediated cleavage. Because 75SirT1 is resistant to further degradation, we assumed it has a distinct role in osteoarthritis (OA) pathology, which we sought out to identify in this study. METHODS: OA and normal human chondrocytes were analyzed for the presence of Cathepsin B and 75SirT1. Confocal imaging of SirT1 monitored its subcellular trafficking following TNFα stimulation. Co-immunofluorescent staining was carried out for Cathepsin B, mitochondrial Cox IV and Lysosome-associated membrane protein I (LAMP-I) together with SirT1. Human chondrocyte were tested for apoptosis via FACS analysis and immunoblotting for caspase 3 and 8. Human chondrocyte mitochondrial extracts were obtained and analyzed for 75SirT1/Cytochrome C association. RESULTS: Confocal imaging and immunoblot analyses following TNFα challenge of human chondrocytes, demonstrated that 75SirT1 was exported to the cytoplasm and colocalized with the mitochondrial membrane. Consistently, immunoprecipitation and immunoblot analyses revealed that 75SirT1 is enriched in mitochondrial extracts and associates with Cytochrome C, following TNFα stimulation. Preventing nuclear export of 75SirT1 or reducing levels of FLSirT1 and 75SirT1 augmented chondrocyte apoptosis in the presence of TNFα. Cathepsin B and 75SirT1 were elevated in OA vs. normal chondrocytes. Additional analyses shows that human chondrocytes exposed to OA-derived synovial fluid generate the 75SirT1 fragment. CONCLUSION: These data suggest that 75SirT1 promotes chondrocyte survival following exposure to proinflammatory cytokines. © 2011 American College of Rheumatology. |
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Authors:
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Hanna Oppenheimer; Odile Gabay; Hadar Meir; Amir Haze; Leonid Kandel; Meir Liebergall; Viktoria Gagarina; Eun Jin Lee; Mona Dvir-Ginzberg |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-10 |
Journal Detail:
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Title: Arthritis and rheumatism Volume: - ISSN: 1529-0131 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370605 Medline TA: Arthritis Rheum Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 by the American College of Rheumatology. |
Affiliation:
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Laboratory of Cartilage Biology, Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University- Hadassah Ein Kerem, Jerusalem, Israel. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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