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LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

Elayyan, J, Lee, EJ, Gabay, O, Smith, CA, Qiq, O, Eli, R, Mobasheri, Ali, Henrotin, Y, Kimber, SJ and Dvir-Ginzberg, M (2017) LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes The FASEB Journal.

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Abstract

Reduced SIRT1 activity and levels during osteoarthritis (OA), promotes gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase of matrix metalloproteinase 13 (MMP13), partially due to enhanced LEF1 transcriptional activity. Here we assess the role of SIRT1 in LEF1-mediated MMP13 gene expression in human osteoarthritic chondrocytes. Results show 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. While previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mice articular cartilage from Sirt1 nulls 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.

Item Type: Article
Subjects : Veterinary Medicine
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
NameEmailORCID
Elayyan, JUNSPECIFIEDUNSPECIFIED
Lee, EJUNSPECIFIEDUNSPECIFIED
Gabay, OUNSPECIFIEDUNSPECIFIED
Smith, CAUNSPECIFIEDUNSPECIFIED
Qiq, OUNSPECIFIEDUNSPECIFIED
Eli, RUNSPECIFIEDUNSPECIFIED
Mobasheri, Alia.mobasheri@surrey.ac.ukUNSPECIFIED
Henrotin, YUNSPECIFIEDUNSPECIFIED
Kimber, SJUNSPECIFIEDUNSPECIFIED
Dvir-Ginzberg, MUNSPECIFIEDUNSPECIFIED
Date : 7 April 2017
Identification Number : 10.1096/fj.201601253R
Copyright Disclaimer : Copyright 2017 FASEB
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 22 Mar 2017 16:53
Last Modified : 19 Jul 2017 13:39
URI: http://epubs.surrey.ac.uk/id/eprint/813828

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