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

Takahashi, Akira ; Mulati, Mieradili ; Saito, Masanori ; Numata, Hoashi ; Kobayashi, Yutaka ; Ochi, Hiroki ; Sato, Shingo ; Kaldis, Philipp LU ; Okawa, Atsushi and Inose, Hiroyuki (2018) In Journal of Biological Chemistry 293(50). p.19387-19399
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
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
in
Journal of Biological Chemistry
volume
293
issue
50
pages
19387 - 19399
publisher
ASBMB
external identifiers
  • scopus:85058517149
  • pmid:30366983
ISSN
1083-351X
DOI
10.1074/jbc.RA118.004834
language
English
LU publication?
no
id
13f05f78-9143-4e6d-b9da-17e3411dc154
date added to LUP
2019-09-17 14:48:26
date last changed
2021-02-17 06:52:13
@article{13f05f78-9143-4e6d-b9da-17e3411dc154,
  abstract     = {<p>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.</p>},
  author       = {Takahashi, Akira and Mulati, Mieradili and Saito, Masanori and Numata, Hoashi and Kobayashi, Yutaka and Ochi, Hiroki and Sato, Shingo and Kaldis, Philipp and Okawa, Atsushi and Inose, Hiroyuki},
  issn         = {1083-351X},
  language     = {eng},
  month        = {12},
  number       = {50},
  pages        = {19387--19399},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Loss of cyclin-dependent kinase 1 impairs bone formation, but does not affect the bone-anabolic effects of parathyroid hormone},
  url          = {http://dx.doi.org/10.1074/jbc.RA118.004834},
  doi          = {10.1074/jbc.RA118.004834},
  volume       = {293},
  year         = {2018},
}