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. ChungAndre J. van WijnenRene St-Arnaud

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

机译：抑制催化亚基的刺激osteoblastogenesis,其余骨形成蛋白2 (BMP2)反应

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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.

机译：依赖dna的蛋白质的催化亚基激酶(DNA-PKcs)是一种多效性的酶参与DNA修复、细胞周期控制转录调控。DNA-PKcs osteoblastogenesis的规定还有待建立。药理DNA-PKcs激酶的抑制活动或基因沉默Prkdc(编码DNA-PKcs)小鼠成骨细胞的MC3T3-E1细胞和人类脂肪间充质基质显著增强骨生成和细胞表达成骨细胞分化的标志基因。循环过程和骨生成增加显著提高骨形成在成骨细胞和其他蛋白质2反应间充质细胞类型。药物抑制激酶增强骨生物力学特性。osteoblast-specific条件Prkdc-knockout老鼠表现出相似的表型的增加刚度。调节成骨细胞分化因此DNA-PKcs抑制剂治疗骨再生和潜力骨代谢疾病。

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《Journal of cellular physiology.》 |2021年第2期|1195-1213|共19页
作者
Theresa Farhat; Amel Dudakovic; Jay H. ChungAndre J. van WijnenRene St-Arnaud;
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作者单位

Research Centre, Shriners Hospital for Children - Canada, Montreal, Quebec, Canada;

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正文语种英语
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关键词
Bone Morphogenetic Protein 2; PRKDC gene; Catalytic DomainDNA-Dependent Protein KinaseOsteoblast;

机译：骨形成蛋白2;PRKDC基因;催化;

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

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