Hypoxia signaling in bone physiology and energy metabolism

Hypoxia-inducible factor (HIF) signaling activation in osteoblast lineage cells increases bone mass, likely through the combined actions of multiple key downstream effectors. These include the potent angiogenesis stimulator vascular endothelial growth factor (VEGF), which mediates coupled osteo-angiogenic responses in bone, among other non-cell-autonomous contributors. Additionally, local HIF activation in bone cells cell-intrinsically triggers increased glycolysis, which is associated with strongly enhanced osteoblastic glucose consumption. Strikingly, besides its local impact on bone mass, this boosting of cellular metabolism in the osteolineage has been linked to increased overall glucose uptake by the skeleton and concomitant effects on systemic glucose homeostasis. This review summarizes the cell-autonomous and non-cell-autonomous roles of the hypoxia signaling pathway in osteoblast lineage cells on bone physiology and the parallel systemic impact observed upon activation of the pathway in bone. New potential mechanisms extending the control of global energy metabolism by the skeleton will be discussed in light of the current evidence.