Mostra i principali dati dell'item
Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention
dc.creator | Iliopoulos, D. | en |
dc.creator | Malizos, K. N. | en |
dc.creator | Tsezou, A. | en |
dc.date.accessioned | 2015-11-23T10:30:22Z | |
dc.date.available | 2015-11-23T10:30:22Z | |
dc.date.issued | 2007 | |
dc.identifier | 10.1136/ard.2007.069377 | |
dc.identifier.issn | 0003-4967 | |
dc.identifier.uri | http://hdl.handle.net/11615/28577 | |
dc.description.abstract | Objective: To investigate whether epigenetic mechanisms can regulate leptin's expression and affect its downstream targets as metalloproteinases 3,9,13 in osteoarthritic chondrocytes. Methods: DNA methylation in leptin promoter was measured by DNA bisulfite sequencing, and mRNA expression levels were measured by real-time quantitative PCR in osteoarthritic as well as in normal cartilage. Osteoarthritic articular cartilage samples were obtained from two distinct locations of the knee ( n = 15); from the main defective area of maximum load ( advanced osteoarthritis ( OA)) and from adjacent macroscopically intact regions ( minimal OA). Using small interference RNA, we tested if leptin downregulation would affect matrix metalloproteinase ( MMP)-13 activity. We also evaluated the effect of the demethylating agent, 59-Aza-2-deoxycytidine ( AZA) and of the histone deacetylase inhibitor trichostatin A ( TSA) on leptin expression in chondrocyte cultures. Furthermore, we performed chromatin immunoprecipitation in leptin's promoter area. Results: We found a correlation between leptin expression and DNA methylation and also that leptin controls MMP-13 activity in chondrocytes. Leptin's downregulation with small interference RNA inhibited MMP-13 expression dramatically. After 5-AZA application in normal chondrocytes, leptin's methylation was decreased, while its expression was upregulated, and MMP-13 was activated. Furthermore, TSA application in normal chondrocyte cultures increased leptin's expression. Also, chromatin immunoprecipitation in leptin's promoter after TSA treatment revealed that histone H3 lysines 9 and 14 were acetylated. Conclusion: We found that epigenetic mechanisms regulate leptin's expression in chondrocytes affecting its downstream target MMP-13. Small interference RNA against leptin deactivated directly MMP-13, which was upregulated after leptin's epigenetic reactivation, raising the issue of leptin's therapeutic potential for osteoarthritis. | en |
dc.source | Annals of the Rheumatic Diseases | en |
dc.source.uri | <Go to ISI>://WOS:000250902600012 | |
dc.subject | PHASE-I TRIAL | en |
dc.subject | GENE-EXPRESSION | en |
dc.subject | DNA METHYLATION | en |
dc.subject | HEMATOPOIETIC | en |
dc.subject | MALIGNANCIES | en |
dc.subject | HYPOMETHYLATING AGENT | en |
dc.subject | OBESE GENE | en |
dc.subject | CANCER | en |
dc.subject | PROMOTER | en |
dc.subject | DEMETHYLATION | en |
dc.subject | BONE | en |
dc.subject | Rheumatology | en |
dc.title | Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention | en |
dc.type | journalArticle | en |
Files in questo item
Files | Dimensione | Formato | Mostra |
---|---|---|---|
Nessun files in questo item. |