Abstract
'Hypoxia-inducible factor 1-alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl-4-hydroxylase 2'.
Highlights
Bone is continuously remodelled, initially during skeletal formation and during development and in response to traumatic events such as bone fracture
We reported that macrophage colony-stimulating factor (M-CSF) stabilized hypoxia-inducible factor (HIF)-1α protein in mature human osteoclasts in normoxic culture [38]
M-CSF stabilized HIF-1α in normoxic CD14+ monocytes (Figure 1A), suggesting that HIF expression might increase throughout M-CSF- and RANKL-induced osteoclastogenesis
Summary
Initially during skeletal formation and during development and in response to traumatic events such as bone fracture. Remodelling is regulated by the co-ordinated actions of osteoclasts, which resorb bone, and osteoblasts, which form new mineralized bone. Osteoclast and osteoblast function is regulated by the hypoxia-inducible transcription factor, HIF. HIF-α is proteasomally degraded following post-translational hydroxylation by a set of prolyl-4-hydroxylase enzymes (PHD1–3) that targets it for interaction with the von Hippel–Lindau protein (VHL). HIF-α accumulates under conditions associated with either reduced PHD enzyme activity (for example, hypoxia [4,5] or oncogenic mutation [6]) or enhanced translation of HIF-α such that it exceeds the substrate capacity of the PHD enzymes (for example, insulin [7] or hepatocyte growth factor (HGF) [8] exposure). Stabilized HIF-α translocates to the nucleus, dimerizes with HIF-β, and binds the hypoxia-response element (HRE) of HIF target genes to initiate transcription
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