title: Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation.
abstract: The synthesis of type I collagen, the main component of bone matrix, precedes the expression of Runx2, the earliest determinant of osteoblast differentiation. We hypothesized that the energetic needs of osteoblasts might explain this apparent paradox. We show here that glucose, the main nutrient of osteoblasts, is transported in these cells through Glut1, whose expression precedes that of Runx2. Glucose uptake favors osteoblast differentiation by suppressing the AMPK-dependent proteasomal degradation of Runx2 and promotes bone formation by inhibiting another function of AMPK. While RUNX2 cannot induce osteoblast differentiation when glucose uptake is compromised, raising blood glucose levels restores collagen synthesis in Runx2-null osteoblasts and initiates bone formation in Runx2-deficient embryos. Moreover, RUNX2 favors Glut1 expression, and this feedforward regulation between RUNX2 and Glut1 determines the onset of osteoblast differentiation during development and the extent of bone formation throughout life. These results reveal an unexpected intricacy between bone and glucose metabolism.
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Shimazu
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Munevver P
authors.initials: MP
authors.lastname: Makinistoglu
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Maurizi
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kajimura
authors.affiliation: Department of Medicine and Molecular Pharmacology, The Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zong
authors.affiliation: Laboratory of Molecular Pharmacology, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takarada
authors.affiliation: Laboratory of Molecular Pharmacology, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Lezaki
authors.affiliation: Department of Medicine and Molecular Pharmacology, The Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.affiliation: Laboratory of Molecular Pharmacology, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
authors.affiliation: Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006706:Homeostasis; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D016415:Sequence Alignment; D012886:Skull / Q000166:cytology
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D051272:Glucose Transporter Type 1; C493716:Runx2 protein, mouse; C495678:Slc2a1 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose