Hypoxia, hypoxia-inducible transcription factors and oxygen-sensing prolyl hydroxylases in bone development and homeostasis.

Abstract

To summarize the role of hypoxia signaling in skeletal cells. Hypoxia occurs at several stages during bone development. Skeletal cells, like chondrocytes and osteoblasts, respond to this challenge by stabilizing the hypoxia inducible transcription factor HIF, which induces the expression of angiogenic factors and promotes glycolysis. The increased delivery of oxygen and nutrients, together with metabolic adaptations, prevent chondrocyte cell death in the growth plate and promote bone formation by osteoblasts. However, excessive HIF levels have to be avoided during bone development as the resulting metabolic maladaptations cause skeletal dysplasia. Recent studies show that HIF also targets other genes to increase bone mass: it decreases osteoclastogenesis by increasing osteoprotegerin expression and represses sclerostin expression by epigenetic mechanisms, resulting in increased bone formation and decreased resorption. Moreover, increased HIF signaling in osteolineage cells promotes primary and metastatic breast tumor growth, and induces erythropoietin (EPO) production, resulting in polycythemia. Finally, HIF can directly or indirectly through increasing EPO levels, induce the expression and processing of FGF23 and may thereby affect mineral homeostasis and vitamin D metabolism. HIF signaling in skeletal cells not only affects their behavior but also influences erythropoiesis and possibly mineral homeostasis.