Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
Life Sci. 2024 Dec 1;358:123148. doi: 10.1016/j.lfs.2024.123148. Epub 2024 Oct 22.
Cyclin-dependent kinase (CDK) family proteins involve in various cellular processes via regulating the cell cycle; however, their expression during osteogenic differentiation and postmenopausal osteoporosis remains poorly understood.
Using bioinformatics, we screened for CDK14 bound to Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and explored its expression in vitro with time-gradient model and in a mouse model of postmenopausal osteoporosis, building on prior research. Subsequently, we investigated its effect on osteoblast proliferation, cell cycle dynamics, and osteogenic differentiation by administering CDK14 siRNA and the covalent inhibitor FMF-04-159-2. Furthermore, we examined the interaction between IGF2BP2 and CDK14. Finally, we validated the regulatory role of CDK14 on the Wnt/β-catenin pathway.
Our findings demonstrate a time-dependent CDK14 expression patterns during osteogenic differentiation of MC3T3-E1 cell line, with an initial increase followed by gradual decline over time. Notably, CDK14 expression exhibited significant reduction in bone tissue of postmenopausal osteoporosis mouse model. CDK14 inhibition altered osteoblast cell cycle dynamics, significantly reduced cellular proliferation capacity, and impaired osteogenic differentiation ability. IGF2BP2 interacted with CDK14 mRNA, and stabilizing mRNA's structure and inhibiting its degradation. Additionally, CDK14 facilitated Low-density lipoprotein receptor-related protein 6 (LRP6) and Glycogen synthase kinase 3β (GSK3β) phosphorylation, thus regulating β-catenin levels.
These findings provide further insight into the molecular mechanisms governing osteoblast proliferation, differentiation and osteoporosis.
细胞周期蛋白依赖性激酶（CDK）家族蛋白通过调节细胞周期参与各种细胞过程；然而，它们在成骨分化和绝经后骨质疏松症中的表达仍知之甚少。
我们使用生物信息学筛选出与胰岛素样生长因子 2 mRNA 结合蛋白 2（IGF2BP2）结合的 CDK14，并通过时间梯度模型和绝经后骨质疏松症小鼠模型探索其体外表达，在此基础上进行了先前的研究。随后，我们通过给予 CDK14 siRNA 和共价抑制剂 FMF-04-159-2 来研究其对成骨细胞增殖、细胞周期动力学和成骨分化的影响。此外，我们还研究了 IGF2BP2 和 CDK14 之间的相互作用。最后，我们验证了 CDK14 对 Wnt/β-catenin 通路的调节作用。
我们的研究结果表明，在 MC3T3-E1 细胞系的成骨分化过程中，CDK14 的表达呈现出时间依赖性模式，最初增加，随后随着时间的推移逐渐下降。值得注意的是，CDK14 的表达在绝经后骨质疏松症小鼠模型的骨组织中显著降低。CDK14 抑制改变了成骨细胞的细胞周期动力学，显著降低了细胞增殖能力，并损害了成骨分化能力。IGF2BP2 与 CDK14 mRNA 相互作用，稳定 mRNA 的结构并抑制其降解。此外，CDK14 促进了低密度脂蛋白受体相关蛋白 6（LRP6）和糖原合酶激酶 3β（GSK3β）的磷酸化，从而调节β-catenin 水平。
这些发现为骨细胞增殖、分化和骨质疏松症的分子机制提供了进一步的深入了解。
