Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis, a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by siRNA, genetic deletion using the Cre-loxP system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro. Roscovitine treatment significantly enhanced bone mass by increasing osteoblastogenesis and improved fracture healing in mice. Mechanistically, downregulation of Cdk5 expression increased Erk phosphorylation, resulting in enhanced osteoblast-specific gene expression. Notably, simultaneous Cdk5 and Erk depletion abrogated the osteoblastogenesis conferred by Cdk5 depletion alone, suggesting that Cdk5 regulates osteoblast differentiation through MAPK pathway modulation. We conclude that Cdk5 is a potential therapeutic target to treat osteoporosis and improve fracture healing.

中文翻译：

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抑制 Cdk5 可增加成骨细胞分化和骨量并改善骨折愈合。

鉴定可以药理学靶向的成骨细胞生成调节剂是对抗骨质疏松症的主要目标，骨质疏松症是老年人群的一种常见疾病。在这里，原代小鼠成骨细胞中的无偏激酶组 RNAi 筛选鉴定出细胞周期蛋白依赖性激酶 5 (Cdk5) 作为小鼠和人类前成骨细胞中成骨细胞分化的抑制因子。通过 siRNA 敲低 Cdk5、使用 Cre-loxP 系统进行基因缺失或用小分子 roscovitine 进行抑制可增强体外成骨细胞生成。Roscovitine 治疗通过增加成骨细胞生成和改善小鼠骨折愈合显着增加骨量。从机制上讲，Cdk5 表达的下调增加了 Erk 磷酸化，导致成骨细胞特异性基因表达增强。尤其，同时 Cdk5 和 Erk 耗竭消除了仅由 Cdk5 耗竭赋予的成骨细胞生成，表明 Cdk5 通过 MAPK 通路调节调节成骨细胞分化。我们得出结论，Cdk5 是治疗骨质疏松症和改善骨折愈合的潜在治疗靶点。