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

Cell Metab. 2006 Dec;4(6):441-51. doi: 10.1016/j.cmet.2006.10.010.

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 (Nf1(ob)(-/-) mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1(ob)(-/-) 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 Nf1(ob)(-/-) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism*
  • Amino Acids / metabolism
  • Animals
  • Biological Transport, Active / drug effects
  • Biological Transport, Active / genetics
  • Bone Diseases, Developmental / congenital
  • Bone Diseases, Developmental / diet therapy*
  • Bone Diseases, Developmental / metabolism*
  • Bone Diseases, Developmental / pathology
  • Bone Resorption / diet therapy
  • Bone Resorption / genetics
  • Bone Resorption / metabolism
  • Bone Resorption / pathology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Coffin-Lowry Syndrome / genetics
  • Coffin-Lowry Syndrome / metabolism
  • Coffin-Lowry Syndrome / pathology
  • Collagen / biosynthesis
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dietary Proteins / therapeutic use*
  • Mice
  • Mice, Knockout
  • Neurofibromin 1 / deficiency
  • Neurofibromin 1 / metabolism*
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Osteogenesis / genetics
  • RANK Ligand / biosynthesis
  • RANK Ligand / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / deficiency
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism

Substances

  • Amino Acids
  • Atf4 protein, mouse
  • Dietary Proteins
  • Neurofibromin 1
  • RANK Ligand
  • Tnfsf11 protein, mouse
  • Activating Transcription Factor 4
  • Collagen
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3
  • Cyclic AMP-Dependent Protein Kinases