HIF-1α regulates bone formation after osteogenic mechanical loading

Abstract

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 to 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.

The zebrafish miR-125c is induced under hypoxic stress via hypoxia-inducible factor 1α and functions in cellular adaptations and embryogenesis

“…The understanding of the role of HIF in the cellular adaptation to hypoxia during embryonic development is still unfolding. A number of evidences have demonstrated its effect on tissue formation and many developmental systems, such as hematopoiesis [ 70 ], angiogenesis [ 71 ], hepatogenesis [ 72 ], bone formation [ 73 ] and heart development [ 20 ]. In vertebrate embryos, regulation of the entry into mitosis is essential for normal morphogenesis, and cdc25 is a key controller of mitotic entry.…”

Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation

“…For dynamic parameters, 6-week-old mice of each genotype were injected with calcein (7.5 mg/kg body weight) and alizarin 3-methyl iminodiacetic acid (30 mg/kg body weight) at 7 and 2 days before euthanasia, respectively. Femoral bone formation rates were quantified by dynamic histomorphometry, as described previously (Tomlinson and Silva, 2015). Following fixation, each femur was embedded in poly-(methyl methacrylate) and 100 μm thick transverse sections were cut (Leco VC50) at the femoral midpoint, then polished to 30 μm and mounted on glass slides.…”

Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects

“…The frequency of HIF-1-positive osteocytes increases in mice under disuse conditions [7]; in vitro, exposing osteocyte-like cells to hypoxia augments secretion of chemotactic factors [8] and GDF15 to promote osteoclastogenesis [9], and influences the osteoblast-to-osteocyte transition [10]. Other osteocytic functions attributed to HIF- function include directing appropriate bone formation in response to mechanical loading [11], sensing microdamage [12], and development of the lacunocanalicular network in which osteocytes reside [13].…”