Hypoxia-inducible Factor-1α Protein Negatively Regulates Load-induced Bone Formation

Riddle, Ryan C.; Leslie, Julie M.; Gross, Ted S.; Clemens, Thomas L.

doi:10.1074/jbc.m111.276683

Cited by 39 publications

(43 citation statements)

References 57 publications

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“…When challenged with non-damaging forelimb compression, ΔHIF-1α mice respond normally, resulting in a greater absolute level of bone formation in ΔHIF-1α loaded limbs compared to WT. This finding is similar to results from a previous study that showed ΔHIF-1α mice generated more bone following 3 weeks of tibial bending than WT mice, although they found no differences in bone formation in sham limbs [21]. The increased bone formation in non-loaded limbs observed in this study is consistent with the age-related changes in bone size previously reported – ΔHIF-1α mice begin life with small bones that become comparable to their wild type littermates in adulthood [21].…”

Section: Discussionsupporting

confidence: 91%

“…Female mice were housed under standard conditions until 18–22 weeks of age, to ensure skeletal maturity [31, 32] and allow approximate normalization of any cortical bone phenotype [21]. At the time of loading, there was no significant difference in weight between WT (23.1 ± 1.4 g) and ΔHIF-1α (22.6 ± 2.0 g) mice.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, these mice do not produce adequate vascularity to support woven bone induction during distraction osteogenesis [19], consistent with the requirement of angiogenesis in this process [20]. However, by 24 weeks of age, bones from mice lacking HIF-1α in the osteoblast lineage have normal cortical thickness and moment of inertia as well as significantly increased bone area compared to wild type controls [21]. Consistent with increased bone apposition in adult mice, these mice have enhanced periosteal lamellar bone formation when subjected to mild tibial mechanical loads [21].…”

Section: Introductionmentioning

confidence: 90%

“…However, by 24 weeks of age, bones from mice lacking HIF-1α in the osteoblast lineage have normal cortical thickness and moment of inertia as well as significantly increased bone area compared to wild type controls [21]. Consistent with increased bone apposition in adult mice, these mice have enhanced periosteal lamellar bone formation when subjected to mild tibial mechanical loads [21]. Taken together, these results indicate that HIF-1α plays a complex role in postnatal osteogenesis.…”

Section: Introductionmentioning

confidence: 99%

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HIF-1α regulates bone formation after osteogenic mechanical loading

Tomlinson

Silva

2015

Bone

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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HIF-1α regulates bone formation after osteogenic mechanical loading

Tomlinson

Silva

2015

Bone

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“…We have shown that reactivation of HIF-1a in ost-MSCs effectively inhibits OxPhos to the levels found in undifferentiated cells. Earlier works provide opposing views on the role of HIF-1 in osteoblasts; while Regan et al describe an anabolic effect of HIF-1 [22], Riddle et al report an inhibitory role of HIF-1 on osteoblast differentiation [23]. Our data provide insight on this controversy: HIF-1a may be required at early stages of osteogenesis to maintain active glycolysis needed for high rates of proliferation.…”

Section: Discussionmentioning

confidence: 57%

Energy Metabolism in Mesenchymal Stem Cells During Osteogenic Differentiation

Shum

White

Mills

et al. 2016

Stem Cells and Development

204

208

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There is emerging interest in stem cell energy metabolism and its effect on differentiation. Bioenergetic changes in differentiating bone marrow mesenchymal stem cells (MSCs) are poorly understood and were the focus of our study. Using bioenergetic profiling and transcriptomics, we have established that MSCs activate the mitochondrial process of oxidative phosphorylation (OxPhos) during osteogenic differentiation, but they maintain levels of glycolysis similar to undifferentiated cells. Consistent with their glycolytic phenotype, undifferentiated MSCs have high levels of hypoxia-inducible factor 1 (HIF-1). Osteogenically induced MSCs downregulate HIF-1 and this downregulation is required for activation of OxPhos. In summary, our work provides important insights on MSC bioenergetics and proposes a HIF-based mechanism of regulation of mitochondrial OxPhos in MSCs.

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Control of osteogenesis by the canonical Wnt and BMP pathways in vivo

2012

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Although many regulators of skeletogenesis have been functionally characterized, one current challenge is to integrate this information into regulatory networks. Here, we discuss how the canonical Wnt and Smad-dependent BMP pathways interact together and play antagonistic or cooperative roles at different steps of osteogenesis, in the context of the developing vertebrate embryo. Early on, BMP signaling specifies multipotent mesenchymal cells into osteochondroprogenitors. In turn, the function of Wnt signaling is to drive these osteochondroprogenitors towards an osteoblastic fate. Subsequently, both pathways promote osteoblast differentiation, albeit with notable mechanistic differences. In osteocytes, the ultimate stage of osteogenic differentiation, the Wnt and BMP pathways exert opposite effects on the control of bone resorption by osteoclasts. We describe how the dynamic molecular wiring of the canonical Wnt and Smad-dependent BMP signaling into the skeletal cell genetic programme is critical for the generation of bone-specific cell types during development.

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Hypoxia-inducible Factor-1α Protein Negatively Regulates Load-induced Bone Formation

Cited by 39 publications

References 57 publications

HIF-1α regulates bone formation after osteogenic mechanical loading

HIF-1α regulates bone formation after osteogenic mechanical loading

Energy Metabolism in Mesenchymal Stem Cells During Osteogenic Differentiation

Control of osteogenesis by the canonical Wnt and BMP pathways in vivo

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