The Indispensable Role of Cyclin-Dependent Kinase 1 in Skeletal Development
Open Access
- 10 February 2016
- journal article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 6 (1), 20622
- https://doi.org/10.1038/srep20622
Abstract
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.This publication has 39 references indexed in Scilit:
- Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regenerationProceedings of the National Academy of Sciences of the United States of America, 2012
- Runx1 and Runx2 cooperate during sternal morphogenesisDevelopment, 2010
- A microRNA regulatory mechanism of osteoblast differentiationProceedings of the National Academy of Sciences of the United States of America, 2009
- Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related proteinProceedings of the National Academy of Sciences of the United States of America, 2008
- Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activityGenes & Development, 2008
- Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2Development, 2008
- Dicer-dependent pathways regulate chondrocyte proliferation and differentiationProceedings of the National Academy of Sciences of the United States of America, 2008
- Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1Proceedings of the National Academy of Sciences of the United States of America, 2006
- Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrPJCI Insight, 2005
- Developmental regulation of the growth plateNature, 2003