title: EZH2 deletion in early mesenchyme compromises postnatal bone microarchitecture and structural integrity and accelerates remodeling.
abstract: In this study, we examined the functional importance of EZH2 during skeletal development and homeostasis using the conditional deletion ofEzh2(Ezh2fl/fl) in early mesenchyme with the use of a Prrx-1-cre driver mouse (Ezh2+/+). Heterozygous(Ezh2+/-) newborn and 4-wk-old mice exhibited increased skeletal size, growth plate size, and weight when compared to the wild-type control (Ezh2+/+), whereas homozygous deletion ofEzh2(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 inEzh2+/-andEzh2-/-animals.Ezh2+/-andEzh2-/-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 turnover markers cross-linked C-telopeptide-1 and tartrate-resistant acid phosphatase, detected within serum. Moreover,Ezh2+/-mice displayed increased osteoclastogenic potential coinciding with an upregulation ofRanklandM-csfexpression by mesenchymal stem cells (MSCs). MSCs isolated fromEzh2+/-mice also exhibited increased trilineage potential compared with wild-type bone marrow stromal/stem cells (BMSCs). Gene expression studies confirmed the upregulation of knownEzh2target genes inEzh2-/-bone tissue, many of which are involved in Wnt/BMP signaling as promoters of osteogenesis and inhibitors of adipogenesis. In summary, EZH2 appears to be an important orchestrator of skeletal development, postnatal bone remodelling and BMSC fate determinationin vitroandin vivo-Hemming, S., Cakouros, D., Codrington, J., Vandyke, K., Arthur, A., Zannettino, A., Gronthos, S. EZH2 deletion in early mesenchyme compromises postnatal bone microarchitecture and structural integrity and accelerates remodeling.
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hemming
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Cakouros
authors.affiliation: School of Mechanical Engineering, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Codrington
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.|Myeloma Research Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia; and.|South Australia Pathology, Adelaide, South Australia, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Vandyke
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Agneiszka
authors.initials: A
authors.lastname: Arthur
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.|Myeloma Research Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zannettino
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia; stan.gronthos@adelaide.edu.au.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D000071556:Cancellous Bone / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D002478:Cells, Cultured; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse
keywords: conditional knockout; differentiation; epigenetics; mesenchymal stem cells; skeletal development