ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae.
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.
Elefteriou
Florent
F
Department of Molecular and Human Genetics, Bone Disease program of Texas, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Benson
M Douglas
MD
Sowa
Hideaki
H
Starbuck
Michael
M
Liu
Xiuyun
X
Ron
David
D
Parada
Luis F
LF
Karsenty
Gerard
G
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000235:genetics; D001848:Bone Diseases, Developmental / Q000151:congenital / Q000178:diet therapy* / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D038921:Coffin-Lowry Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004044:Dietary Proteins / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D025542:Neurofibromin 1 / Q000172:deficiency / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000378:metabolism
D000596:Amino Acids; C081452:Atf4 protein, mouse; D004044:Dietary Proteins; D025542:Neurofibromin 1; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D051701:Activating Transcription Factor 4; D003094:Collagen; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D017868:Cyclic AMP-Dependent Protein Kinases