TY - JOUR
T1 - HIF-1α regulates bone formation after osteogenic mechanical loading
AU - Tomlinson, Ryan E.
AU - Silva, Matthew J.
N1 - Funding Information:
Founding members of the mouse colony used in this study were generously donated by Drs. Thomas Clemens and Ryan Riddle (Johns Hopkins University). The authors are grateful to Dr. Deborah Novack for assistance with histology. This study was funded by a grant from the National Institutes of Health ( R01 AR050211 ). This work was performed in facilities supported by the Washington University Center for Musculoskeletal Research ( P30 AR057235 ).
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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.
AB - 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.
KW - HIF-1α
KW - Hypoxia inducible factor
KW - Mechanical loading
KW - Osteogenesis
UR - http://www.scopus.com/inward/record.url?scp=84920373602&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2014.12.015
DO - 10.1016/j.bone.2014.12.015
M3 - Article
C2 - 25541207
AN - SCOPUS:84920373602
SN - 8756-3282
VL - 73
SP - 98
EP - 104
JO - Bone
JF - Bone
ER -