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 language | English (US) |
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Pages (from-to) | 1195-1213 |
Number of pages | 19 |
Journal | Journal of Cellular Physiology |
Volume | 236 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2021 |
Keywords
- DNA-dependent protein kinase
- adipose-derived mesenchymal stromal cells
- bone morphogenetic protein 2
- osteoblastogenesis
- osteoblasts
ASJC Scopus subject areas
- Physiology
- Clinical Biochemistry
- Cell Biology