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Runx2, glucose uptake and the first events of osteoblast differentiation
DOI:10.1038/bonekey.2015.118
In order to explain the paradox that type 1 collagen is synthesized before expression of Runx2, the gene known to be the master determinant of osteoblast differentiation, Wei et al. investigated the nutrient requirements of osteoblasts at this crucial point in their development.
Their findings reveal that glucose is transported into osteoblasts in the very earliest stages of differentiation by the transporter protein Glut1. Expression of the gene encoding Glut1 occurs before expression of Runx2.
The increased uptake of glucose by pre-osteoblasts and the subsequent rise in intracellular glucose prevents the continued proteosomal degradation of RUNX2 by AMP activated protein kinase (AMPK). The interplay between glucose levels and RUNX2 activity is confirmed by observations that raising blood glucose levels can kick start bone formation in mouse embryos deficient in Runx2 and that increased glucose restores synthesis of collagen in osteoblasts with a Runx2 knockout.
The authors also show that as RUNX2 levels rise, so does the expression of Glut1. This positive feedback loop creates the tipping point that initiates osteoblast differentiation. This key event may also have a long-lasting effect on the pattern of bone formation throughout the life of the individual.
Editor's comment: These observations contribute to unveiling the intricate mutual regulation between glucose-regulated osteoblast differentiation and osteocalcin-regulated glucose metabolism. It will be interesting to find out when the expression of Glut1 starts to increase and to discover more details of the mechanism by which Glut1 expression is regulated during the early stage of osteoblast differentiation.
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