Abstract

The Runt-related transcription factor 2 (RUNX2) is critical for bone formation as well as chondrocyte maturation. Matrix metalloproteinase (MMP)-13 is a major contributor to cartilage degradation in osteoarthritis (OA). We and others have shown that the abnormal MMP13 gene expression in OA chondrocytes is controlled by changes in the DNA methylation status of specific CpG sites of the proximal promoter, as well as by the actions of different transactivators, including RUNX2. The present study aimed to determine the influence of the methylation status of specific CpG sites in the RUNX2 promoter on RUNX2-driven MMP13 gene expression in OA chondrocytes. We observed a significant correlation between MMP13 mRNA levels and RUNX2 gene expression in human OA chondrocytes. RUNX2 overexpression enhanced MMP13 promoter activity, independent of the MMP13 promoter methylation status. A significant negative correlation was observed between RUNX2 mRNA levels in OA chondrocytes and the percentage methylation of the CpG sites in the RUNX2 P1 promoter. Accordingly, the activity of the wild type RUNX2 promoter was decreased upon methylation treatment in vitro. We conclude that RUNX2 gene transcription is regulated by the methylation status of specific CpG sites in the promoter and may determine RUNX2 availability in OA cartilage for transactivation of genes such as MMP13.

Details

Title
DNA methylation of the RUNX2 P1 promoter mediates MMP13 transcription in chondrocytes
Author
Takahashi, Atsushi 1 ; de Andrés, María C 2 ; Hashimoto, Ko 3 ; Itoi, Eiji 4 ; Otero, Miguel 5 ; Goldring, Mary B 5   VIAFID ORCID Logo  ; Oreffo, Richard O C 2   VIAFID ORCID Logo 

1  Bone and Joint Research Group, Centre for Human Development Stem Cells and Regeneration, Institute of Developmental Science, University of Southampton Medical School, Southampton, UK; Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan 
2  Bone and Joint Research Group, Centre for Human Development Stem Cells and Regeneration, Institute of Developmental Science, University of Southampton Medical School, Southampton, UK 
3  Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan; HSS Research Institute, Hospital for Special Surgery, and Weill Cornell Medical College, New York, NY, USA 
4  Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan 
5  HSS Research Institute, Hospital for Special Surgery, and Weill Cornell Medical College, New York, NY, USA 
Pages
1-10
Publication year
2017
Publication date
Aug 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-017-08418-8
ProQuest document ID
1957176382
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.