The regulation glucose metabolism by the bone-derived hormone osteocalcin naturally raises the question of why bone would regulate glucose metabolism in the first place. One possible way to address this question is to determine the function of glucose in osteoblasts. In addressing this question we showed that osteoblasts uptake considerable amounts of glucose in an insulin-independent manner through the glucose transporter Glut1. Glucose is necessary in osteoblasts for collagen synthesis and therefore for bone formation. In addition, by preventing its ubiquitination glucose favors Runx2 accumulation in osteoblasts, expression of Runx2 target genes such as Osteocalcin and thereby whole-body glucose homeostasis. The importance of the function of glucose in osteoblasts begs in turn the question of the regulation of expression of Glut1 in cells of the osteoblast lineage. Our preliminary experiments indicate that Runx2 is a major regulator of Glut1 expression in vivo and therefore point toward a feed forward regulation between Glut1-dependent glucose uptake in osteoblasts that favors collagen synthesis, bone formation and Runx2 accumulation and Runx2 that favors Glut1 expression. We hypothesize that this feed forward loop acts as an amplification mechanism allowing proper bone formation during embryonic development and after birth. To test this hypothesis we propose the following specific aims: To determine through molecular means whether Runx2 regulates Glut1, Glut2 and Glut3 expression in osteoblasts directly or indirectly. To demonstrate through genetic means that Runx2 and Glut1 act synergistically to determine the onset and extent of bone formation. To determine through several genetic means to what extent raising blood glucose levels of pregnant Runx2+/- female mice can rescue the bone formation defects of their Runx2- deficient progeny.

Public Health Relevance

The identification of mechanisms regulating bone formation is a long-standing biological question. Solving this problem may help us understand the pathogenesis of some developmental and degenerative diseases. It may also suggest adapted therapies for skeletal dysplasia affecting primarily bone formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK104727-04
Application #
9518855
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2015-09-24
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Karsenty, Gerard; Olson, Eric N (2016) Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication. Cell 164:1248-1256
Mera, Paula; Laue, Kathrin; Wei, Jianwen et al. (2016) Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab 5:1042-7
Jais, Alexander; Solas, Maite; Backes, Heiko et al. (2016) Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity. Cell 165:882-95
Shimazu, Junko; Wei, Jianwen; Karsenty, Gerard (2016) Smurf1 Inhibits Osteoblast Differentiation, Bone Formation, and Glucose Homeostasis through Serine 148. Cell Rep 15:27-35
Wei, Jianwen; Shimazu, Junko; Makinistoglu, Munevver P et al. (2015) Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation. Cell 161:1576-1591