Glucose Restriction Promotes Osteocyte Specification by Activating a PGC-1α-Dependent Transcriptional Program.

Abstract

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bonematrix. This encasement limits their access to nutrients and likely affects their differentiation, a pro-cess that remains poorly defined. Here, we show that restriction in glucose supply promotes the oste-ocyte transcriptional program while also being associated with increased mitochondrial DNA levels.Glucose deprivation triggered the activation of the AMPK/PGC-1 pathway. AMPK and SIRT1 activa-tors or PGC-1aoverexpression are sufficient to enhance osteocyte gene expression in IDG-SW3 cells,murine primary osteoblasts, osteocytes, and organotypic/ex vivobone cultures. Conversely, osteo-blasts and osteocytes deficient inPpargc1aandbwere refractory to the effects of glucose restriction.Finally, conditional ablation of both genes in osteoblasts and osteocytes generate osteopenia andreduce osteocytic gene expression in mice. Altogether, we uncovered a role for PGC-1 in the regula-tion of osteocyte gene expression.