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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Animals, Newborn
-
Bone Morphogenetic Protein 1 / deficiency
-
Bone Morphogenetic Protein 1 / genetics*
-
Bone Morphogenetic Protein 2 / genetics
-
Bone Morphogenetic Protein 2 / metabolism
-
Bone Morphogenetic Protein 2 / pharmacology
-
Bone Morphogenetic Protein Receptors, Type I / deficiency
-
Bone Morphogenetic Protein Receptors, Type I / genetics
-
Bone and Bones / cytology
-
Bone and Bones / metabolism*
-
Cartilage / cytology
-
Cartilage / growth & development
-
Cartilage / metabolism
-
Cell Differentiation / drug effects
-
Cell Proliferation / drug effects
-
Chondrocytes / cytology
-
Chondrocytes / drug effects
-
Chondrocytes / metabolism
-
Chondrogenesis / genetics
-
Embryo, Mammalian
-
Female
-
Gene Expression Regulation, Developmental
-
Glucose / metabolism*
-
Glucose Transporter Type 1 / deficiency
-
Glucose Transporter Type 1 / genetics*
-
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
-
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
-
Male
-
Mechanistic Target of Rapamycin Complex 1 / genetics
-
Mechanistic Target of Rapamycin Complex 1 / metabolism
-
Mice
-
Mice, Knockout
-
Osteoblasts / cytology
-
Osteoblasts / drug effects
-
Osteoblasts / metabolism
-
Osteogenesis / genetics*
-
Primary Cell Culture
-
Signal Transduction / genetics*
Substances
-
Bmp2 protein, mouse
-
Bone Morphogenetic Protein 2
-
Glucose Transporter Type 1
-
Hif1a protein, mouse
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Slc2a1 protein, mouse
-
Mechanistic Target of Rapamycin Complex 1
-
Bmpr1a protein, mouse
-
Bone Morphogenetic Protein Receptors, Type I
-
Bmp1 protein, mouse
-
Bone Morphogenetic Protein 1
-
Glucose