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 E. McGee-Lawrence, Jennifer J. Westendorf, Andre J. Van Wijnen

Research output: Contribution to journalArticlepeer-review

59 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

Bibliographical note

Funding Information:
This work was supported, in whole or in part, by National Institutes of Health Grants F32 AR066508 (to A. D.), R01 AR049069 (to A. J. v. W.), R01 AR068103 (to J. J. W.), and R01 DE020194 (to J. J. W.), Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias 15090007 (to M. A. M.), and generous philanthropic support from William H. and Karen J. Eby and the charitable foundation in their names. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Oksana Pichurin, Bashar Hasan, David Razidlo, and Bridget Stensgard for technical support and the members of our laboratory, as well as our colleagues Anne Gingery, Alexey Leontovich, Sanjeev Kakar, Jay Smith, Aaron Krych, John Sperling, Wenchun Qu, Jane Lian, and Janet Stein for sharing reagents and/or stimulating discussions. We also acknowledge the support of Asha Nair and Jared Evans (Bioinformatics Core, Medical Genome Facility, Biomaterials Characterization and Quantitative Histomorphometry Core Facility and the Arlene Kogod Center on Aging at Mayo Clinic).

Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Fingerprint

Dive into the research topics of 'Enhancer of zeste homolog 2 inhibition stimulates bone formation and mitigates bone loss caused by ovariectomy in skeletally mature mice'. Together they form a unique fingerprint.

Cite this