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

Elefteriou F, Benson MD, Sowa H, Starbuck M, Liu X, Ron D, Parada LF, Karsenty G
Cell Metab. 2006 4 (6): 441-51

PMID: 17141628 · PMCID: PMC2756713 · DOI:10.1016/j.cmet.2006.10.010

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.

MeSH Terms (19)

Activating Transcription Factor 4 Amino Acids Animals Biological Transport, Active Bone Diseases, Developmental Bone Resorption Cell Differentiation Coffin-Lowry Syndrome Collagen Cyclic AMP-Dependent Protein Kinases Dietary Proteins Mice Mice, Knockout Neurofibromin 1 Osteoblasts Osteoclasts Osteogenesis RANK Ligand Ribosomal Protein S6 Kinases, 90-kDa

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