RRC ID 51634
Author Saito M, Mulati M, Talib SZ, Kaldis P, Takeda S, Okawa A, Inose H.
Title The Indispensable Role of Cyclin-Dependent Kinase 1 in Skeletal Development.
Journal Sci Rep
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.
Volume 6
Pages 20622
Published 2016-2-10
DOI 10.1038/srep20622
PII srep20622
PMID 26860366
PMC PMC4816159
MeSH Animals Blotting, Western Bone Development* Bone and Bones / physiology* CDC2 Protein Kinase / antagonists & inhibitors CDC2 Protein Kinase / genetics CDC2 Protein Kinase / metabolism* Cell Differentiation Cell Line Cell Proliferation Chondrocytes / cytology Chondrocytes / metabolism Chondrogenesis Collagen Type II / metabolism Collagen Type X / metabolism In Situ Hybridization, Fluorescence In Vitro Techniques Mice Mice, Knockout Models, Animal Parathyroid Hormone-Related Protein / metabolism RNA Interference RNA, Small Interfering / metabolism Real-Time Polymerase Chain Reaction Signal Transduction Transfection
IF 4.122
Resource
Human and Animal Cells ATDC5(RCB0565)