TY - JOUR
T1 - ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae
AU - Elefteriou, Florent
AU - Benson, M. Douglas
AU - Sowa, Hideaki
AU - Starbuck, Michael
AU - Liu, Xiuyun
AU - Ron, David
AU - Parada, Luis F
AU - Karsenty, Gerard
N1 - Funding Information:
We thank Dr. B. de Crombrugghe for the Osterix −/− mice, D.W. Owens (Pfizer Inc.) for PD198306, and Dr. A. Hanauer for the Phospho-Rsk2 antibody. This work was supported by grants from National Institutes of Health (G.K. and L.P.); The Children's Tumor Foundation (F.E.); the Japan Osteoporosis Foundation, The Uehara Memorial Foundation, Kanzawa Medical Research Foundation, and The Mochida Memorial Foundation for Medical and Pharmaceutical Research (H.S.).
PY - 2006/12
Y1 - 2006/12
N2 - 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.
AB - 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.
KW - HUMDISEASE
KW - SIGNALING
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U2 - 10.1016/j.cmet.2006.10.010
DO - 10.1016/j.cmet.2006.10.010
M3 - Article
C2 - 17141628
AN - SCOPUS:33751412300
SN - 1550-4131
VL - 4
SP - 441
EP - 451
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -