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

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dc.contributor.authorDudakovic, Amel
dc.contributor.authorCamilleri, Emily T.
dc.contributor.authorRiester, Scott M.
dc.contributor.authorParadise, Christopher R.
dc.contributor.authorGluscevic, Martina
dc.contributor.authorO'Toole, Thomas M.
dc.contributor.authorThaler, Roman
dc.contributor.authorEvans, Jared M.
dc.contributor.authorYan, Huihuang
dc.contributor.authorSubramaniam, Malayannan
dc.contributor.authorHawse, John R.
dc.contributor.authorStein, Gary S.
dc.contributor.authorMontecino, Martin A.
dc.contributor.authorMcGee-Lawrence, Meghan E.
dc.contributor.authorWestendorf, Jennifer J.
dc.contributor.authorVan Wijnen, Andre J.
dc.date.accessioned2023-05-12T19:38:24Z
dc.date.available2023-05-12T19:38:24Z
dc.date.issued2016-11
dc.descriptionIndexación: Scopus.es
dc.description.abstractPerturbations 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 bone-anabolic and osteoprotective potential in adults.es
dc.description.urihttps://www-sciencedirect-com.recursosbiblioteca.unab.cl/science/article/pii/S0021925820346329?via%3Dihub
dc.identifier.citationJournal of Biological Chemistryes
dc.identifier.doi10.1074/jbc.M116.740571
dc.identifier.issn0021-9258
dc.identifier.urihttps://repositorio.unab.cl/xmlui/handle/ria/49578
dc.language.isoenes
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc. CODEN JBCHAes
dc.rights.licenseAtribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.es
dc.subjectEpigeneticses
dc.subjectHistonees
dc.subjectHistone Methylationes
dc.subjectOsteoblastostes
dc.subjectOsteoporosises
dc.subjectMethyltransferasees
dc.subjectSkeletones
dc.titleEnhancer of zeste homolog 2 inhibition stimulates bone formation and mitigates bone loss caused by ovariectomy in skeletally mature micees
dc.typeArtículoes
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