The Indispensable Role of Cyclin-Dependent Kinase 1 in Skeletal Development.
The Indispensable Role of Cyclin-Dependent Kinase 1 in Skeletal Development.
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DOI：
10.1038/srep20622
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发表时间：
2016-02-10
影响因子：
4.6
通讯作者：
Inose H
中科院分区：
文献类型：
--
作者：
Saito M;Mulati M;Talib SZ;Kaldis P;Takeda S;Okawa A;Inose H
骨骼发育通过软骨细胞增殖和分化过程受到严格调控。尽管转录和生长因子参与骨骼发育的调控已被广泛研究，但细胞周期调控蛋白在这一过程中的作用仍然难以捉摸。迄今为止，通过细胞特异性功能丧失的体内实验，还没有细胞周期调控蛋白被最终证明可以调节骨骼发育。在这里，我们证明，细胞周期蛋白依赖性激酶1（Cdk1）调节骨骼发育的软骨细胞特异性功能丧失的实验在小鼠模型中进行的基础上。Cdk1在柱状增殖软骨细胞中高度表达，并在分化为肥大软骨细胞时显著下调。Cdk1是软骨细胞增殖的关键因子，缺失Cdk1可加速软骨细胞的分化。体外和离体分析表明，Cdk 1是甲状旁腺素相关肽（PTHrP）信号通路中一个重要的细胞周期调控蛋白，对软骨细胞的增殖和分化至关重要。这些结果表明，Cdk1作为一个分子开关从增殖到肥大分化的软骨细胞的功能，因此是必不可少的骨骼发育。鉴于Cdk1活性抑制剂的可用性，我们的研究结果可以为涉及异常软骨细胞增殖的疾病（如骨关节炎）的治疗提供见解。
Skeletal development is tightly regulated through the processes of chondrocyte proliferation and differentiation. Although the involvement of transcription and growth factors on the regulation of skeletal development has been extensively studied, the role of cell cycle regulatory proteins in this process remains elusive. To date, through cell-specific loss-of-function experiments in vivo, no cell cycle regulatory proteins have yet been conclusively shown to regulate skeletal development. Here, we demonstrate that cyclin-dependent kinase 1 (Cdk1) regulates skeletal development based on chondrocyte-specific loss-of-function experiments performed in a mouse model. Cdk1 is highly expressed in columnar proliferative chondrocytes and is greatly downregulated upon differentiation into hypertrophic chondrocytes. Cdk1 is essential for proper chondrocyte proliferation and deletion of Cdk1 resulted in accelerated differentiation of chondrocytes. In vitro and ex vivo analyses revealed that Cdk1 is an essential cell cycle regulatory protein for parathyroid hormone-related peptide (PTHrP) signaling pathway, which is critical to chondrocyte proliferation and differentiation. These results demonstrate that Cdk1 functions as a molecular switch from proliferation to hypertrophic differentiation of chondrocytes and thus is indispensable for skeletal development. Given the availability of inhibitors of Cdk1 activity, our results could provide insight for the treatment of diseases involving abnormal chondrocyte proliferation, such as osteoarthritis.