Genetic determination of the cellular basis of the ghrelin-dependent bone remodeling.
Genetic determination of the cellular basis of the ghrelin-dependent bone remodeling.
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DOI：
10.1016/j.molmet.2015.01.002
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发表时间：
2015-03
影响因子：
8.1
通讯作者：
Takeda S
中科院分区：
文献类型：
--
作者：
Ma C;Fukuda T;Ochi H;Sunamura S;Xu C;Xu R;Okawa A;Takeda S
通过骨形成和再吸收的平衡来维持骨量。这种稳态平衡是由涉及体液和局部因素的各种系统调节的。骨生成激素瘦素通过神经通路调节骨量的发现揭示了神经元和神经肽密切参与骨稳态。Ghrelin是一种胃源性的食欲激素，可以抵消瘦素的作用。然而，ghrelin在骨稳态中的生理作用仍然未知。本研究通过Ghrelin受体（Ghsr）的基因敲除和组织特异性表达，探讨Ghrelin在体内骨重建中的作用机制。我们进行了分子，遗传学和细胞生物学分析的Ghsr-null小鼠和Ghsr-null小鼠与组织特异性Ghsr恢复。此外，我们评估了ghrelin的分子机制，分子和细胞为基础的检测。Ghsr-null小鼠表现出低骨量表型，骨形成差。恢复Ghsr的表达，特别是在成骨细胞，而不是在破骨细胞或中枢神经系统，改善骨异常Ghsr基因敲除小鼠。基于细胞的分析显示ghrelin诱导CREB的磷酸化和Runx 2的表达，这反过来又加速成骨细胞分化。我们的数据表明，ghrelin通过调节CREB和Runx 2途径，通过成骨细胞中的Ghsr调节骨重建。
Bone mass is maintained through a balance of bone formation and resorption. This homeostatic balance is regulated by various systems involving humoral and local factors. The discovery that the anorexigenic hormone leptin regulates bone mass via neuronal pathways revealed that neurons and neuropeptides are intimately involved in bone homeostasis. Ghrelin is a stomach-derived orexigenic hormone that counteracts leptin's action. However, the physiological role of ghrelin in bone homeostasis remains unknown. In this study, through the global knockout of ghrelin receptor (Ghsr) followed by tissue-specific re-expression, we addressed the molecular basis of the action of ghrelin in bone remodeling in vivo. We performed molecular, genetic and cell biological analyses of Ghsr-null mice and Ghsr-null mice with tissue specific Ghsr restoration. Furthermore, we evaluated the molecular mechanism of ghrelin by molecular and cell-based assays. Ghsr-null mice showed a low bone mass phenotype with poor bone formation. Restoring the expression of Ghsr specifically in osteoblasts, and not in osteoclasts or the central nervous system, ameliorated bone abnormalities in Ghsr-null mice. Cell-based assays revealed ghrelin induced the phosphorylation of CREB and the expression of Runx2, which in turn accelerated osteoblast differentiation. Our data show that ghrelin regulates bone remodeling through Ghsr in osteoblasts by modulating the CREB and Runx2 pathways.
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DOI：
10.1126/science.1241214
发表时间：
2013-09-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ridaura VK;Faith JJ;Rey FE;Cheng J;Duncan AE;Kau AL;Griffin NW;Lombard V;Henrissat B;Bain JR;Muehlbauer MJ;Ilkayeva O;Semenkovich CF;Funai K;Hayashi DK;Lyle BJ;Martini MC;Ursell LK;Clemente JC;Van Treuren W;Walters WA;Knight R;Newgard CB;Heath AC;Gordon JI
通讯作者：
Gordon JI
影响因子：
15.9
作者：
Chuang, Jen-Chieh;Perello, Mario;Zigman, Jeffrey M.
通讯作者：
Zigman, Jeffrey M.
影响因子：
4.8
作者：
Hassouna, Rim;Zizzari, Philippe;Tolle, Virginie
通讯作者：
Tolle, Virginie
影响因子：
5.8
作者：
Cassoni, P;Ghé, C;Muccioli, G
通讯作者：
Muccioli, G
DOI：
10.1084/jem.20102608
发表时间：
2011-04-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kajimura D;Hinoi E;Ferron M;Kode A;Riley KJ;Zhou B;Guo XE;Karsenty G
通讯作者：
Karsenty G