Glucose metabolism induced by Bmp signaling is essential for murine skeletal development

Seung-Yon Lee,E Dale Abel,Fanxin Long

doi:10.1038/s41467-018-07316-5

Abstract

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.

Highlights

Much of the mammalian skeleton originates from a cartilage template eventually replaced by bone via endochondral ossification
While the cartilage template continues to grow at the ends due to proliferation and hypertrophy, it is progressively replaced by bone and the expanding marrow cavity from the middle, following resorption of the hypertrophic cartilage
Multiple growth factors have been implicated in regulating chondrocyte proliferation and hypertrophy during endochondral bone development[1]

Summary

Introduction

Much of the mammalian skeleton originates from a cartilage template eventually replaced by bone via endochondral ossification. Once the bone marrow cavity is established, chondrocytes form the growth plate composed of discreet domains including proliferation and hypertrophy zones, at either end of the cartilage template. Studies have shown distinct expression patterns for different members of the Bmp family, including Bmp[2], Bmp[4] and Bmp[5] in the perichondrium, Bmp[2] and Bmp[6] in the hypertrophic chondrocytes and Bmp[7] in the proliferating chondrocytes[18] Both type I and type II receptors for Bmp signaling are expressed with characteristic patterns within the growth plate. Multiple members of the Glut family have been implicated in glucose transport in chondrocytes, the physiological relevance of each transporter has not been demonstrated[24] It is not clear whether and how growth factors modulate glucose metabolism in the developing cartilage. Further studies are necessary to understand the potential role and mechanism of metabolic regulation in skeletal development

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Results

Conclusion