ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae
ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae
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DOI：
10.1016/j.cmet.2006.10.010
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发表时间：
2006-12-01
期刊：
影响因子：
29
通讯作者：
Karsenty, Gerard
中科院分区：
文献类型：
--
作者：
Elefteriou, Florent;Benson, M. Douglas;Karsenty, Gerard
转录因子ATF 4通过促进成骨细胞中的氨基酸输入和胶原蛋白合成来增强骨形成，这一功能需要其被RSK 2磷酸化，RSK 2是Coffin-Lowry综合征中失活的激酶。在这里，我们表明，相比之下，RSK 2活性，ATF 4依赖性胶原蛋白的合成，骨形成增加缺乏成骨细胞神经纤维蛋白的小鼠（Nf 1（ob）（-/-）小鼠）。在Nf 1（ob）（-/-）小鼠中，不依赖于RSK 2，PKA引起的ATF 4磷酸化增强，从而增加Rankl表达、破骨细胞分化和骨吸收。与ATF 4在氨基酸转运中的功能一致，低蛋白饮食降低了Nf 1（ob）（-/-）小鼠的骨蛋白合成并使骨形成和骨量正常化，而不影响其他器官重量，而高蛋白饮食克服了Atf 4（-/-）和Rsk 2（-/-）小鼠的发育缺陷，围产期致死率和低骨量。通过显示ATF 4依赖性骨骼发育不良可以通过饮食控制来治疗，这项研究揭示了营养和骨骼发育之间的分子联系。
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.