title: LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes.
abstract: Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study, we assessed the role of SIRT1 in LEF1-mediated MMP13 gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1β, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-1β challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1-/-presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.-Elayyan, J., Lee, E.-J., Gabay, O., Smith, C. A., Qiq, O., Reich, E., Mobasheri, A., Henrotin, Y., Kimber, S. J., Dvir-Ginzberg, M. LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes.
authors.affiliation: Laboratory of Cartilage Biology, Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Jinan
authors.initials: J
authors.lastname: Elayyan
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biotechnology Review and Research I, Silver Spring, Maryland, USA.
authors.forename: Odile
authors.initials: O
authors.lastname: Gabay
authors.affiliation: Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Smith
authors.affiliation: Laboratory of Cartilage Biology, Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Omar
authors.initials: O
authors.lastname: Qiq
authors.affiliation: Laboratory of Cartilage Biology, Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Reich
authors.affiliation: Department of Veterinary Preclinical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.|Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Queen's Medical Centre, Nottingham, United Kingdom.
authors.forename: Ali
authors.initials: A
authors.lastname: Mobasheri
authors.affiliation: Bone and Cartilage Research Unit, Arthropôle Liège, University of Liège, Institute of Pathology, Liège, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Henrotin
authors.affiliation: Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Kimber
authors.affiliation: Laboratory of Cartilage Biology, Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; monad@ekmd.huji.ac.il.
authors.forename: Mona
authors.initials: M
authors.lastname: Dvir-Ginzberg
mesh_terms: D000071121:ADAMTS4 Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular; D019902:Chondrocytes / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D051821:Lymphoid Enhancer-Binding Factor 1; D053509:Matrix Metalloproteinase 13; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8; D000071121:ADAMTS4 Protein; D056564:Sirtuin 1
keywords: IL-1β; cartilage; catabolism; inflammation; osteoarthritis