Glucose metabolism induced by Bmp signaling is essential for murine skeletal development.
Glucose metabolism induced by Bmp signaling is essential for murine skeletal development.
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DOI：
10.1038/s41467-018-07316-5
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发表时间：
2018-11-16
影响因子：
16.6
通讯作者：
Long F
中科院分区：
文献类型：
--
作者：
Lee SY;Abel ED;Long F
哺乳动物的骨骼大部分起源于软骨模板，最终通过软骨内骨化被骨取代。尽管在骨骼发育方面对生长因子和核蛋白有了很多了解，但对代谢调节的作用却知之甚少。在此我们报道，在肢体软骨形成开始之前或之后，葡萄糖转运蛋白Glut1（Slc2a1）的基因缺失都会严重损害软骨细胞的增殖和肥大，导致肢体显著缩短。软骨缺陷与Bmp信号缺失所导致的缺陷相似。重要的是，软骨细胞中Bmpr1a的缺失在体内显著降低了Glut1的水平，而重组的BMP2增加了Glut1的mRNA和蛋白质水平，促进了原代软骨细胞的葡萄糖代谢。生化研究确定了一个Bmp - mTORC1 - Hif1a信号级联，导致软骨细胞中Glut1的上调。因此，这些结果揭示了在软骨发育调节中Bmp信号与葡萄糖代谢之间迄今未知的联系。
目前尚不清楚代谢调节如何影响骨骼发育。在这里，作者表明在小鼠肢体软骨形成之前和之后葡萄糖转运蛋白Glut1（Slc2a1）的缺失都会损害软骨细胞增殖和导致肢体缩短，且受BMP信号调节。
Much of the mammalian skeleton originates from a cartilage template eventually replaced by bone via endochondral ossification. Despite much knowledge about growth factors and nuclear proteins in skeletal development, little is understood about the role of metabolic regulation. Here we report that genetic deletion of the glucose transporter Glut1 (Slc2a1), either before or after the onset of chondrogenesis in the limb, severely impairs chondrocyte proliferation and hypertrophy, resulting in dramatic shortening of the limbs. The cartilage defects are reminiscent to those caused by deficiency in Bmp signaling. Importantly, deletion of Bmpr1a in chondrocytes markedly reduces Glut1 levels in vivo, whereas recombinant BMP2 increases Glut1 mRNA and protein levels, boosting glucose metabolism in primary chondrocytes. Biochemical studies identify a Bmp-mTORC1-Hif1a signaling cascade resulting in upregulation of Glut1 in chondrocytes. The results therefore uncover a hitherto unknown connection between Bmp signaling and glucose metabolism in the regulation of cartilage development. It is unclear how metabolic regulation affects development of the skeleton. Here, the authors show that deletion of the glucose transporter Glut1 (Slc2a1) both prior to and following chondrogenesis in the mouse limb impairs chondrocyte proliferation and shortening of the limbs, modulated by BMP signaling.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0503617102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Kobayashi, T;Lyons, KM;Kronenberg, HM
通讯作者：
Kronenberg, HM
影响因子：
7.2
作者：
Long, Fanxin;Ornitz, David M.
通讯作者：
Ornitz, David M.
影响因子：
3.2
作者：
KIM, JK;HASELGROVE, JC;SHAPIRO, IM
通讯作者：
SHAPIRO, IM
影响因子：
2.7
作者：
Hilton, Matthew J.;Tu, Xiaolin;Long, Fanxin
通讯作者：
Long, Fanxin