Inhibition of the epigenetic suppressor EZH2 primes osteogenic differentiation mediated by BMP2

Amel Dudakovic, Rebekah M. Samsonraj, Christopher R. Paradise, Catalina Galeano-Garces, Merel O. Mol, Daniela Galeano-Garces, Pengfei Zan, M. Lizeth Galvan, Mario Hevesi, Oksana Pichurin, Roman Thaler, Dana L. Begun, Peter Kloen, Marcel Karperien, A. Noelle Larson, Jennifer J. Westendorf, Simon M. Cool, Andre J. van Wijnen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Bone-stimulatory therapeutics include bone morphogenetic proteins (e.g. BMP2), parathyroid hormone, and antibody-based suppression of WNT antagonists. Inhibition of the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) is both bone anabolic and osteoprotective. EZH2 inhibition stimulates key components of bone-stimulatory signaling pathways, including the BMP2 signaling cascade. Because of high costs and adverse effects associated with BMP2 use, here we investigated whether BMP2 dosing can be reduced by co-treatment with EZH2 inhibitors. Co-administration of BMP2 with the EZH2 inhibitor GSK126 enhanced differentiation of murine (MC3T3) osteoblasts, reflected by increased alkaline phosphatase activity, Alizarin Red staining, and expression of bone-related marker genes (e.g. Bglap and Phospho1). Strikingly, co-treatment with BMP2 (10 ng/ml) and GSK126 (5 μm) was synergistic and was as effective as 50 ng/ml BMP2 at inducing MC3T3 osteoblastogenesis. Similarly, the BMP2-GSK126 co-treatment stimulated osteogenic differentiation of human bone marrow-derived mesenchymal stem/stromal cells, reflected by induction of key osteogenic markers (e.g. Osterix/SP7 and IBSP). A combination of BMP2 (300 ng local) and GSK126 (5 μg local and 5 days of 50 mg/kg systemic) yielded more consistent bone healing than single treatments with either compound in a mouse calvarial critical-sized defect model according to results from μCT, histomorphometry, and surgical grading of qualitative X-rays. We conclude that EZH2 inhibition facilitates BMP2-mediated induction of osteogenic differentiation of progenitor cells and maturation of committed osteoblasts. We propose that epigenetic priming, coupled with bone anabolic agents, enhances osteogenesis and could be leveraged in therapeutic strategies to improve bone mass.

Original languageEnglish
Pages (from-to)7877-7893
Number of pages17
JournalThe Journal of biological chemistry
Volume295
Issue number23
Early online date24 Apr 2020
DOIs
Publication statusPublished - 5 Jun 2020

Keywords

  • BMP2
  • bone development
  • bone morphogenetic protein (BMP)
  • chromatin regulation
  • enhancer of zeste homolog
  • epigenetics
  • Ezh2
  • histone methylation
  • mesenchymal stem cells (MSCs)
  • methyltransferase
  • osteoblast
  • osteogenesis
  • Mesenchymal stem cell
  • Histone methylation
  • Methyltransferase
  • Enhancer of zeste homolog
  • Chromatin regulation
  • Bone development
  • Epigenetics
  • Osteoblast
  • Osteogenesis

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    Dudakovic, A., Samsonraj, R. M., Paradise, C. R., Galeano-Garces, C., Mol, M. O., Galeano-Garces, D., ... van Wijnen, A. J. (2020). Inhibition of the epigenetic suppressor EZH2 primes osteogenic differentiation mediated by BMP2. The Journal of biological chemistry, 295(23), 7877-7893. https://doi.org/10.1074/jbc.RA119.011685