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The Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice.

Publication ,  Journal Article
Hu, G; Yu, Y; Tang, YJ; Wu, C; Long, F; Karner, CM
Published in: J Bone Miner Res
October 2020

Skeletal stem/progenitor cells (SSPC) are critical regulators of bone homeostasis by providing a continuous supply of osteoblasts throughout life. In response to inductive signals, SSPC proliferate before osteoblast differentiation. Proliferation requires the duplication of all cellular components before cell division. This imposes a unique biosynthetic requirement for amino acids that can be used for biomass production. Thus, the ability to sense and respond to amino acid availability is likely a major determinant for proliferation. Using a cellular and genetic approach, we demonstrate the amino acid sensor GCN2 is required to support the robust proliferative capacity of SSPC during bone homeostasis. GCN2 ablation results in decreased postnatal bone mass due primarily to reduced osteoblast numbers. Decreased osteoblast numbers is likely attributed to reduced SSPC proliferation as loss of GCN2 specifically affected proliferation in cultured bone marrow stromal cells (BMSCs) without impacting osteoblast differentiation in vitro. Mechanistically, GCN2 regulates proliferation by increasing amino acid uptake downstream of the transcriptional effector ATF4. Collectively, these data suggest amino acid sensing through the GCN2/ATF4 pathway is indispensable for robust SSPC proliferation necessary for bone homeostasis. © 2020 American Society for Bone and Mineral Research.

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Published In

J Bone Miner Res

DOI

EISSN

1523-4681

Publication Date

October 2020

Volume

35

Issue

10

Start / End Page

2004 / 2014

Location

United States

Related Subject Headings

  • Stem Cells
  • Protein Serine-Threonine Kinases
  • Osteoblasts
  • Mice
  • Cell Proliferation
  • Cell Differentiation
  • Animals
  • Anatomy & Morphology
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
 

Citation

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Hu, G., Yu, Y., Tang, Y. J., Wu, C., Long, F., & Karner, C. M. (2020). The Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice. J Bone Miner Res, 35(10), 2004–2014. https://doi.org/10.1002/jbmr.4091
Hu, Guoli, Yilin Yu, Yuning J. Tang, Colleen Wu, Fanxin Long, and Courtney M. Karner. “The Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice.J Bone Miner Res 35, no. 10 (October 2020): 2004–14. https://doi.org/10.1002/jbmr.4091.
Hu G, Yu Y, Tang YJ, Wu C, Long F, Karner CM. The Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice. J Bone Miner Res. 2020 Oct;35(10):2004–14.
Hu, Guoli, et al. “The Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice.J Bone Miner Res, vol. 35, no. 10, Oct. 2020, pp. 2004–14. Pubmed, doi:10.1002/jbmr.4091.
Hu G, Yu Y, Tang YJ, Wu C, Long F, Karner CM. The Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice. J Bone Miner Res. 2020 Oct;35(10):2004–2014.
Journal cover image

Published In

J Bone Miner Res

DOI

EISSN

1523-4681

Publication Date

October 2020

Volume

35

Issue

10

Start / End Page

2004 / 2014

Location

United States

Related Subject Headings

  • Stem Cells
  • Protein Serine-Threonine Kinases
  • Osteoblasts
  • Mice
  • Cell Proliferation
  • Cell Differentiation
  • Animals
  • Anatomy & Morphology
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences