HIF-1α regulates bone formation after osteogenic mechanical loading

HIF-1 is a transcription factor typically associated with angiogenic gene transcription under hypoxic conditions. In this study, mice with HIF-1α deleted in the osteoblast lineage (ΔHIF-1α) were subjected to damaging or non-damaging mechanical loading known to produce woven or lamellar bone, respectively, at the ulnar diaphysis. By microCT, ΔHIF-1α mice produced significantly less woven bone than wild type (WT) mice 7 days after damaging loading. This decrease in woven bone volume and extent was accompanied by a significant decrease in vascularity measured by immunohistochemistry against vWF. Additionally, osteocytes, rather than osteoblasts, appear to be the main bone cell expressing HIF-1α following damaging loading. In contrast, 10 days after non-damaging mechanical loading, dynamic histomorphometry measurements demonstrated no impairment in loading-induced lamellar bone formation in ΔHIF-1α mice. In fact, both non-loaded and loaded ulnae from ΔHIF-1α mice had increased bone formation compared with WT ulnae. When comparing the relative increase in periosteal bone formation in loaded vs. non-loaded ulnae, it was not different between ΔHIF-1α mice and controls. There were no significant differences observed between WT and ΔHIF-1α mice in endosteal bone formation parameters. The increases in periosteal lamellar bone formation in ΔHIF-1α mice are attributed to non-angiogenic effects of the knockout. In conclusion, these results demonstrate that HIF-1α is a pro-osteogenic factor for woven bone formation after damaging loading, but an anti-osteogenic factor for lamellar bone formation under basal conditions and after non-damaging loading.