E74-like Factor 3 (ELF3) impacts on Matrix Metalloproteinase 13 (MMP13) transcriptional control in articular chondrocytes under proinflammatory stress

Miguel Otero, Darren A. Plumb, Kaneyuki Tsuchimochi, Cecilia L. Dragomir, Ko Hashimoto, Haibing Peng, Eleonora Olivotto, Michael Bevilacqua, Lujian Tan, Zhiyong Yang, Yumei Zhan, Peter Oettgen, Yefu Li, Kenneth B. Marcu, Mary B. Goldring

Research output: Contribution to journalArticle

Abstract

Matrix metalloproteinase (MMP)-13 has a pivotal, rate-limiting function in cartilage remodeling and degradation due to its specificity for cleaving type II collagen. The proximal MMP13 promoter contains evolutionarily conserved E26 transformation- specific sequence binding sites that are closely flanked by AP-1 and Runx2 binding motifs, and interplay among these and other factors has been implicated in regulation by stress and inflammatory signals. Here we report that ELF3 directly controls MMP13 promoter activity by targeting an E26 transformation- specific sequence binding site at position -78 bp and by cooperating with AP-1. In addition, ELF3 binding to the proximal MMP13 promoter is enhanced by IL-1β stimulation in chondrocytes, and the IL-1β-induced MMP13 expression is inhibited in primary human chondrocytes by siRNA-ELF3 knockdown and in chondrocytes from Elf3 -/-mice. Further, we found that MEK/ERK signaling enhances ELF3-driven MMP13 transactivation and is required for IL-1β-induced ELF3 binding to the MMP13 promoter, as assessed by chromatin immunoprecipitation. Finally, we show that enhanced levels of ELF3 co-localize withMMP13protein and activity in human osteoarthritic cartilage. These studies define a novel role for ELF3 as a procatabolic factor that may contribute to cartilage remodeling and degradation by regulating MMP13 gene transcription.

Original languageEnglish
Pages (from-to)3559-3572
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number5
DOIs
Publication statusPublished - Jan 27 2012

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Otero, M., Plumb, D. A., Tsuchimochi, K., Dragomir, C. L., Hashimoto, K., Peng, H., Olivotto, E., Bevilacqua, M., Tan, L., Yang, Z., Zhan, Y., Oettgen, P., Li, Y., Marcu, K. B., & Goldring, M. B. (2012). E74-like Factor 3 (ELF3) impacts on Matrix Metalloproteinase 13 (MMP13) transcriptional control in articular chondrocytes under proinflammatory stress. Journal of Biological Chemistry, 287(5), 3559-3572. https://doi.org/10.1074/jbc.M111.265744