EZH2 deletion in early mesenchyme compromises postnatal bone microarchitecture & structural integrity & accelerates remodeling

Sarah Hemming, Dimitrios Cakouros, John Codrington, Kate Vandyke, Agneiszka Arthur, Andrew Zannettino, Stan Gronthos

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

In this study, we examined the functional importance of EZH2 during skeletal development and homeostasis using the conditional deletion of Ezh2 (Ezh2fl/fl) in early mesenchyme with the use of a Prrx-1-cre drivermouse (Ezh2+/+). Heterozygous (Ezh2+/-)newborn and 4-wk-oldmice exhibited increased skeletal size, growth plate size, and weight when compared to thewild-Type control (Ezh2+/+), whereas homozygous deletion of Ezh2 (Ezh2-/-) resulted in skeletal deformities and reduced skeletal size, growth plate size, and weight in newborn and 4-wk-old mice. Ezh2-/- mice exhibited enhanced trabecular patterning. Osteogenic cortical and trabecular bone formation was enhanced in Ezh2+/- and Ezh2-/- animals. Ezh2+/- and Ezh2-/- mice displayed thinner cortical bone and decreased mechanical strength compared to the wild-Type control. Differences in cortical bone thickness were attributed to an increased number of osteoclasts, corresponding with elevated levels of the bone turnovermarkers cross-linked C-Telopeptide-1 and tartrate-resistant acid phosphatase, detected within serum. Moreover, Ezh2+/- mice displayed increased osteoclastogenic potential coinciding with an upregulation of Rankl and M-csf expression by mesenchymal stem cells (MSCs).MSCs isolated from Ezh2+/- mice also exhibited increased trilineage potential comparedwithwild-Type bone marrow stromal/stemcells (BMSCs). Gene expression studies confirmed the upregulation of knownEzh2 target genes in Ezh2-/- bonetissue,manyofwhich are involved inWnt/BMPsignaling aspromoters of osteogenesis andinhibitors of adipogenesis. In summary, EZH2 appears to be an important orchestrator of skeletal development, postnatal bone remodelling and BMSC fate determination in vitro and in vivo.

Original languageEnglish
Pages (from-to)1011-1027
Number of pages17
JournalFASEB Journal
Volume31
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017

Keywords

  • Conditional knockout
  • Differentiation
  • Epigenetics
  • Mesenchymal stem cells
  • Skeletal development

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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