Loss of cyclin-dependent kinase 1 impairs bone formation, but does not affect the bone-anabolic effects of parathyroid hormone

Research output: Contribution to journalArticle

Abstract

Bone mass is maintained by a balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Although recent genetic studies have uncovered various mechanisms that regulate osteoblast differentiation, the molecular basis of osteoblast proliferation remains unclear. Here, using an osteoblast-specific loss-of-function mouse model, we demonstrate that cyclin-dependent kinase 1 (Cdk1) regulates osteoblast proliferation and differentiation. Quantitative RT-PCR analyses revealed that Cdk1 is highly expressed in bone and is down-regulated upon osteoblast differentiation. We also noted that Cdk1 is dispensable for the bone-anabolic effects of parathyroid hormone (PTH). Cdk1 deletion in osteoblasts led to osteoporosis in adult mice due to low bone formation, but did not affect osteoclast formation in vivo Cdk1 overexpression in osteoblasts promoted proliferation, and conversely, Cdk1 knockdown inhibited osteoblast proliferation and promoted differentiation. Of note, we provide direct evidence that PTH's bone-anabolic effects occur without enhancing osteoblast proliferation in vivo Furthermore, we found that Cdk1 expression in osteoblasts is essential for bone fracture repair. These findings may help reduce the risk of nonunion after bone fracture and identify patients at higher risk for nonresponse to PTH treatment. Collectively, our results indicate that Cdk1 is essential for osteoblast proliferation and that it functions as a molecular switch that shifts osteoblast proliferation to maturation. We therefore conclude that Cdk1 plays an important role in bone formation.

Details

Authors
  • Akira Takahashi
  • Mieradili Mulati
  • Masanori Saito
  • Hoashi Numata
  • Yutaka Kobayashi
  • Hiroki Ochi
  • Shingo Sato
  • Philipp Kaldis
  • Atsushi Okawa
  • Hiroyuki Inose
External organisations
  • Tokyo Medical and Dental University
  • A*Star Institute of Molecular and Cell Biology (IMCB)
  • National University of Singapore
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • 3T3 Cells, Animals, Bone and Bones/cytology, CDC2 Protein Kinase/deficiency, Cell Differentiation/drug effects, Cell Proliferation/drug effects, Fractures, Bone/physiopathology, Gene Knockout Techniques, Mice, Osteoblasts/cytology, Osteogenesis/genetics, Parathyroid Hormone/pharmacology, Wound Healing/drug effects
Original languageEnglish
Pages (from-to)19387-19399
JournalJournal of Biological Chemistry
Volume293
Issue number50
Publication statusPublished - 2018 Dec 14
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes