Hypoxia, hypoxia-inducible factor (HIF) and bone homeostasis: focus on osteoclast-mediated bone resorption

The growth, maintenance and repair of bone are regulated by homeostatic interactions between osteoclasts, which resorb bone, and osteoblasts, which produce bone. Disruption of this balance in favor of osteoclast over-activation, in the absence of a balancing amount of bone formation, results in pathological bone loss such as that which occurs in osteoporosis, primary bone cancer, cancer metastasis to bone and rheumatoid arthritis. Hypoxia is a major micro-environmental feature of these conditions which is predictive of disease progression and poor prognosis. There is currently considerable interest in the mechanisms whereby hypoxia, the hypoxia-inducible transcription factors HIF-1α and HIF-2α, and the HIF-regulating prolyl hydroxylase (PHD) enzymes affect bone re-modelling and bone pathologies. This review summarises the evidence for HIF-mediated stimulation of osteogenic-angiogenic coupling and the use of PHD inhibitors to stimulate new bone formation and prevent osteolytic disease. It then details the evidence for hypoxia-mediated regulation of osteoclast biology, including the role(s) of HIF in the differentiation of monocytic cells into multi-nucleated osteoclasts and in the activation of bone resorption by mature osteoclasts. Specific attention is paid to the unusual consequences of upregulation of both the glycolytic pathway and mitochondrial metabolism under hypoxic conditions, alongside the consequent generation of reactive oxygen species (ROS), in the context of osteoclast activity and survival. Evidence for the use of HIF inhibitors as potential therapeutic agents targeting bone resorption in osteolytic disease is discussed. Finally, it is considered how HIF induction and HIF inhibition could both be proposed as approaches to improve bone integrity in pathological osteolysis.