LAUSR

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.