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 journalArticlepeer-review

146 Scopus citations

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

Keywords

  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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