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

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

56 Citas (Scopus)

Resumen

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.

Idioma originalInglés
Páginas (desde-hasta)24594-24606
Número de páginas13
PublicaciónJournal of Biological Chemistry
Volumen291
N.º47
DOI
EstadoPublicada - 18 nov. 2016

Áreas temáticas de ASJC Scopus

  • Bioquímica
  • Biología molecular
  • Biología celular

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