ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae

Florent Elefteriou, M. Douglas Benson, Hideaki Sowa, Michael Starbuck, Xiuyun Liu, David Ron, Luis F Parada, Gerard Karsenty

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1ob -/- mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1ob -/- mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1ob -/- mice without affecting other organ weight, while a high-protein diet overcame Atf4-/- and Rsk2-/- mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development.

Original languageEnglish (US)
Pages (from-to)441-451
Number of pages11
JournalCell Metabolism
Volume4
Issue number6
DOIs
StatePublished - Dec 2006

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Osteoblasts
Osteogenesis
Bone and Bones
Coffin-Lowry Syndrome
Activating Transcription Factor 4
Collagen
Neurofibromin 1
Phosphorylation
Amino Acids
Protein-Restricted Diet
Organ Size
Osteoclasts
Bone Resorption
Proteins
Diet

Keywords

  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Elefteriou, F., Benson, M. D., Sowa, H., Starbuck, M., Liu, X., Ron, D., ... Karsenty, G. (2006). ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metabolism, 4(6), 441-451. https://doi.org/10.1016/j.cmet.2006.10.010

ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. / Elefteriou, Florent; Benson, M. Douglas; Sowa, Hideaki; Starbuck, Michael; Liu, Xiuyun; Ron, David; Parada, Luis F; Karsenty, Gerard.

In: Cell Metabolism, Vol. 4, No. 6, 12.2006, p. 441-451.

Research output: Contribution to journalArticle

Elefteriou, F, Benson, MD, Sowa, H, Starbuck, M, Liu, X, Ron, D, Parada, LF & Karsenty, G 2006, 'ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae', Cell Metabolism, vol. 4, no. 6, pp. 441-451. https://doi.org/10.1016/j.cmet.2006.10.010
Elefteriou, Florent ; Benson, M. Douglas ; Sowa, Hideaki ; Starbuck, Michael ; Liu, Xiuyun ; Ron, David ; Parada, Luis F ; Karsenty, Gerard. / ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. In: Cell Metabolism. 2006 ; Vol. 4, No. 6. pp. 441-451.
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