Inhibition of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) stimulates osteoblastogenesis by potentiating bone morphogenetic protein 2 (BMP2) responses

Theresa Farhat, Amel Dudakovic, Jay H. Chung, Andre J van Wijnen, René St-Arnaud

Research output: Contribution to journalArticlepeer-review

Abstract

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is a pleiotropic enzyme involved in DNA repair, cell cycle control, and transcription regulation. A potential role for DNA-PKcs in the regulation of osteoblastogenesis remains to be established. We show that pharmacological inhibition of DNA-PKcs kinase activity or gene silencing of Prkdc (encoding DNA-PKcs) in murine osteoblastic MC3T3-E1 cells and human adipose-derived mesenchymal stromal cells markedly enhanced osteogenesis and the expression of osteoblast differentiation marker genes. Inhibition of DNA-PKcs inhibited cell cycle progression and increased osteogenesis by significantly enhancing the bone morphogenetic protein 2 response in osteoblasts and other mesenchymal cell types. Importantly, in vivo pharmacological inhibition of the kinase enhanced bone biomechanical properties. Bones from osteoblast-specific conditional Prkdc-knockout mice exhibited a similar phenotype of increased stiffness. In conclusion, DNA-PKcs negatively regulates osteoblast differentiation, and therefore DNA-PKcs inhibitors may have therapeutic potential for bone regeneration and metabolic bone diseases.

Original languageEnglish (US)
Pages (from-to)1195-1213
Number of pages19
JournalJournal of Cellular Physiology
Volume236
Issue number2
DOIs
StatePublished - Feb 2021

Keywords

  • adipose-derived mesenchymal stromal cells
  • bone morphogenetic protein 2
  • DNA-dependent protein kinase
  • osteoblastogenesis
  • osteoblasts

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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