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刺猬信号通路激活了一种涉及胰岛素样生长因子的正反馈机制,以诱导成骨细胞分化。

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation.

作者信息

Shi Yu, Chen Jianquan, Karner Courtney M, Long Fanxin

机构信息

Departments of Orthopaedic Surgery.

Departments of Orthopaedic Surgery, Medicine, and Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110

出版信息

Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):4678-83. doi: 10.1073/pnas.1502301112. Epub 2015 Mar 30.

Abstract

Hedgehog (Hh) signaling is essential for osteoblast differentiation in the endochondral skeleton during embryogenesis. However, the molecular mechanism underlying the osteoblastogenic role of Hh is not completely understood. Here, we report that Hh markedly induces the expression of insulin-like growth factor 2 (Igf2) that activates the mTORC2-Akt signaling cascade during osteoblast differentiation. Igf2-Akt signaling, in turn, stabilizes full-length Gli2 through Serine 230, thus enhancing the output of transcriptional activation by Hh. Importantly, genetic deletion of the Igf signaling receptor Igf1r specifically in Hh-responding cells diminishes bone formation in the mouse embryo. Thus, Hh engages Igf signaling in a positive feedback mechanism to activate the osteogenic program.

摘要

刺猬(Hh)信号通路对于胚胎发育过程中软骨内骨的成骨细胞分化至关重要。然而,Hh在成骨细胞生成中的作用的分子机制尚未完全阐明。在此,我们报告Hh显著诱导胰岛素样生长因子2(Igf2)的表达,Igf2在成骨细胞分化过程中激活mTORC2-Akt信号级联反应。反过来,Igf2-Akt信号通路通过丝氨酸230稳定全长Gli2,从而增强Hh转录激活的输出。重要的是,在Hh反应性细胞中特异性缺失Igf信号受体Igf1r会减少小鼠胚胎中的骨形成。因此,Hh通过正反馈机制参与Igf信号通路以激活成骨程序。

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本文引用的文献

1
mTORC2 signaling promotes skeletal growth and bone formation in mice.
J Bone Miner Res. 2015 Feb;30(2):369-78. doi: 10.1002/jbmr.2348.
2
3
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.
Diabetologia. 2012 Oct;55(10):2565-2582. doi: 10.1007/s00125-012-2644-8. Epub 2012 Aug 8.
4
Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells.
Nat Med. 2012 Jul;18(7):1095-101. doi: 10.1038/nm.2793.
5
The insulin-like growth factor system in bone: basic and clinical implications.
Endocrinol Metab Clin North Am. 2012 Jun;41(2):323-33, vi. doi: 10.1016/j.ecl.2012.04.013. Epub 2012 May 15.
7
Gli1 protein participates in Hedgehog-mediated specification of osteoblast lineage during endochondral ossification.
J Biol Chem. 2012 May 18;287(21):17860-17869. doi: 10.1074/jbc.M112.347716. Epub 2012 Apr 9.
8
A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation.
Sci Signal. 2012 Mar 27;5(217):ra25. doi: 10.1126/scisignal.2002469.
9
Foxo1 mediates insulin-like growth factor 1 (IGF1)/insulin regulation of osteocalcin expression by antagonizing Runx2 in osteoblasts.
J Biol Chem. 2011 May 27;286(21):19149-58. doi: 10.1074/jbc.M110.197905. Epub 2011 Apr 6.
10
The primary cilium as a Hedgehog signal transduction machine.
Methods Cell Biol. 2009;94:199-222. doi: 10.1016/S0091-679X(08)94010-3. Epub 2009 Dec 23.

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