A novel role for GADD45β as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation

Kosei Ijiri, Luiz F. Zerbini, Haibing Peng, Ricardo G. Correa, Binfeng Lu, Nicole Walsh, Yani Zhao, Noboru Taniguchi, Xu Ling Huang, Hasan Otu, Hong Wang, Jian Fei Wang, Setsuro Komiya, Patricia Ducy, Mahboob U. Rahman, Richard A. Flavell, Ellen M. Gravallese, Peter Oettgen, Towia A. Libermann, Mary B. Goldring

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

The growth arrest and DNA damage-inducible 45 β (GADD45β) gene product has been implicated in the stress response, cell cycle arrest, and apoptosis. Here we demonstrated the unexpected expression of GADD45β in the embryonic growth plate and uncovered its novel role as an essential mediator of matrix metalloproteinase-13 (MMP-13) expression during terminal chondrocyte differentiation. We identified GADD45β as a prominent early response gene induced by bone morphogenetic protein-2 (BMP-2) through a Smad1/Runx2-dependent pathway. Because this pathway is involved in skeletal development, we examined mouse embryonic growth plates, and we observed expression of Gadd45β mRNA coincident with Runx2 protein in pre-hypertrophic chondrocytes, whereas GADD45β protein was localized prominently in the nucleus in late stage hypertrophic chondrocytes where Mmp-13 mRNA was expressed. In Gadd45β-/- mouse embryos, defective mineralization and decreased bone growth accompanied deficient Mmp-13 and Col10a1 gene expression in the hypertrophic zone. Transduction of small interfering RNA-GADD45β in epiphyseal chondrocytes in vitro blocked terminal differentiation and the associated expression of Mmp-13 and Col10a1 mRNA in vitro. Finally, GADD45β stimulated MMP-13 promoter activity in chondrocytes through the JNK-mediated phosphorylation of JunD, partnered with Fra2, in synergy with Runx2. These observations indicated that GADD45β plays an essential role during chondrocyte terminal differentiation.

Original languageEnglish (US)
Pages (from-to)38544-38555
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number46
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Ijiri, K., Zerbini, L. F., Peng, H., Correa, R. G., Lu, B., Walsh, N., Zhao, Y., Taniguchi, N., Huang, X. L., Otu, H., Wang, H., Wang, J. F., Komiya, S., Ducy, P., Rahman, M. U., Flavell, R. A., Gravallese, E. M., Oettgen, P., Libermann, T. A., & Goldring, M. B. (2005). A novel role for GADD45β as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation. Journal of Biological Chemistry, 280(46), 38544-38555. https://doi.org/10.1074/jbc.M504202200