Enhancer of zeste homolog 2 inhibition stimulates bone formation and mitigates bone loss caused by ovariectomy in skeletally mature mice

Amel Dudakovic, Emily T. Camilleri, Scott M. Riester, Christopher R. Paradise, Martina Gluscevic, Thomas M. O'Toole, Roman Thaler, Jared M. Evans, Huihuang Yan, Malayannan Subramaniam, John R. Hawse, Gary S. Stein, Martin A. Montecino, Meghan Elizabeth McGee Lawrence, Jennifer J. Westendorf, Andre J. Van Wijnen

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Perturbations in skeletal development and bone degeneration may result in reduced bone mass and quality, leading to greater fracture risk. Bone loss is mitigated by bone protective therapies, but there is a clinical need for new bone-anabolic agents. Previous work has demonstrated that Ezh2 (enhancer of zeste homolog 2), a histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation of osteogenic progenitors. Here, we investigated whether inhibition of Ezh2 can be leveraged for bone stimulatory applications. Pharmacologic inhibition and siRNA knockdown of Ezh2 enhanced osteogenic commitment of MC3T3 preosteoblasts. Next generation RNA sequencing of mRNAs and real time quantitative PCR profiling established that Ezh2 inactivation promotes expression of bone-related gene regulators and extracellular matrix proteins. Mechanistically, enhanced gene expression was linked to decreased H3K27 trimethylation (H3K27me3) near transcriptional start sites in genome-wide sequencing of chromatin immunoprecipitations assays. Administration of an Ezh2 inhibitor modestly increases bone density parameters of adult mice. Furthermore, Ezh2 inhibition also alleviated bone loss in an estrogen-deficient mammalian model for osteoporosis. Ezh2 inhibition enhanced expression of Wnt10b and Pth1r and increased the BMP-dependent phosphorylation of Smad1/5. Thus, these data suggest that inhibition of Ezh2 promotes paracrine signaling in osteoblasts and has boneanabolic and osteoprotective potential in adults.

Original languageEnglish (US)
Pages (from-to)24594-24606
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number47
DOIs
StatePublished - Nov 18 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Dudakovic, A., Camilleri, E. T., Riester, S. M., Paradise, C. R., Gluscevic, M., O'Toole, T. M., Thaler, R., Evans, J. M., Yan, H., Subramaniam, M., Hawse, J. R., Stein, G. S., Montecino, M. A., McGee Lawrence, M. E., Westendorf, J. J., & Van Wijnen, A. J. (2016). Enhancer of zeste homolog 2 inhibition stimulates bone formation and mitigates bone loss caused by ovariectomy in skeletally mature mice. Journal of Biological Chemistry, 291(47), 24594-24606. https://doi.org/10.1074/jbc.M116.740571