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Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism
Naomi Dirckx, … , Thomas L. Clemens, Christa Maes
Naomi Dirckx, … , Thomas L. Clemens, Christa Maes
Published March 1, 2018; First published February 12, 2018
Citation Information: J Clin Invest. 2018;128(3):1087-1105. https://doi.org/10.1172/JCI97794.
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Categories: Research Article Bone biology

Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism

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Abstract

The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel–Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin. In vitro and in vivo data indicated that Vhl-deficient osteoblasts displayed massively increased glucose uptake and glycolysis associated with upregulated HIF-target gene expression, resembling the Warburg effect that typifies cancer cells. Overall, the glucose consumption by the skeleton was increased in the mutant mice, as revealed by 18F-FDG radioactive tracer experiments. Moreover, the glycemia levels correlated inversely with the level of skeletal glucose uptake, and pharmacological treatment with the glycolysis inhibitor dichloroacetate (DCA), which restored glucose metabolism in Vhl-deficient osteogenic cells in vitro, prevented the development of the systemic metabolic phenotype in the mutant mice. Altogether, these findings reveal a novel link between cellular glucose metabolism in osteoblasts and whole-body glucose homeostasis, controlled by local hypoxia signaling in the skeleton.

Authors

Naomi Dirckx, Robert J. Tower, Evi M. Mercken, Roman Vangoitsenhoven, Caroline Moreau-Triby, Tom Breugelmans, Elena Nefyodova, Ruben Cardoen, Chantal Mathieu, Bart Van der Schueren, Cyrille B. Confavreux, Thomas L. Clemens, Christa Maes

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Figure 1

High bone mass and skeletal abnormalities in mice lacking Vhl in osteoblast lineage cells.

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High bone mass and skeletal abnormalities in mice lacking Vhl in osteobl...
(A) Tibia length at 12 weeks (n = 4–7 per genotype). (B) Representative 3D micro-CT reconstructions of tibias from 12-week-old mice. (C) Bone volume relative to tissue volume (BV/TV, in %) determined by micro-CT at the indicated ages (n = 3–5/group). (D and E) Micro-CT analysis of the trabecular (D) and cortical (E) tibia regions at 12 weeks (n = 3–5), showing BV/TV; trabecular number (Tb.N), separation (Tb.Sp), and thickness (Tb.Th); and cortical thickness (Cort.Th) and porosity (Cort.Por). (F) Representative transverse micro-CT section of the tibia. (G) Vertebral BV/TV determined by micro-CT (n = 4). (H) Relative (Rel.) mRNA levels of Vegf and Epo in full bones of 12-week-old mice (n = 7). (I) Tibia histology showing H&E staining, PECAM-1 IHC for blood vessels (including magnifications), and reticulin-positive fibers (black stain and yellow arrow) indicative of BM fibrosis in Vhl cKO bones. Scale bars: 500 μm (H&E; PECAM-1 left), 50 μm (PECAM-1 right; reticulin). Graphs represent mean ± SEM, and *P < 0.05, **P < 0.01, ***P < 0.001 by Student’s t test between genotypes.
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