Assessing the potential dual beneficial effects on bone health and global energy metabolism of hypoxia signaling pathway modulation

Metabolic disorders as osteoporosis, obesity and diabetes represent common comorbidities associated with poor bone quality and impaired fracture repair affecting increasing numbers of people. Interestingly, the host lab recently found that genetic activation of hypoxia signaling in osteolineage cells led to improved systemic glucose homeostasis, along with increased bone mass and vascularisation. This raises the intriguing hypothesis that hypoxia signaling activation may be a promising strategy to improve both energy metabolism and bone health. Here, we propose to analyse if the cellular mediators are skeletal stem/progenitor cells (SSPCs) or mature osteoblasts, and whether increased glucose uptake and glycolytic metabolism in osteolineage cells is directly responsible for systemic glucose homeostasis improvement after hypoxia signaling activation. Moreover, we will explore the potential benefits of hypoxia signaling activation in SSPCs during fracture repair compromised by high fat diet-induced diabetes. Secondly, we aim to manipulate hypoxia signaling using pharmacological compounds, in a translational approach to improve energy metabolism, bone homeostasis and regeneration in the context of diabetes. These basic and translational studies will provide insights in the cellular and molecular mechanisms associated with hypoxia signaling activation in bone cells, that impact systemic glucose metabolism and bone repair, and provide outlooks towards a potential therapeutic use.