Chronic Intermittent Hypobaric Hypoxia Enhances Bone Fracture Healing

Zhang, Li; Lin, Jianhao; Guo, Jialiang; Bao, Kai; Hu, Jinglue; Zhang, Yingze; Zhang, Liping

doi:10.3389/fendo.2020.582670

Cited by 17 publications

(15 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bone marrow stem cells can recruit circulating bone marrow‐derived stem cells and endothelial progenitor cells to the injury site through HIF‐1α‐dependent SDF‐1 and its receptor CXC chemokine receptor 4 (CXCR4) 11,36,48 . Through upregulated the HIF‐1α/SDF‐1/CXCR4 axis using exogenous SDF‐1, confirmed that the rise in SDF‐1 is coupled with increased HIF‐1α and CXCR4 expression and that the upregulated HIF‐1α/SDF‐1/CXCR4 axis can also reduce apoptosis and promote cell self‐renewal 13 .…”

Section: The Possible Mechanism By Which Hif‐1α Promotes Bone Regener...mentioning

confidence: 90%

“…46 A rat fracture model treated with intermittent hypoxia and found that VEGF expression in the fracture site was significantly increased compared with that in the control group at weeks 2 and 4, while platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31), a vessel-specific marker, was also specifically increased, suggesting that intermittent hypoxia promoted local vascular regeneration by upregulating the HIF-1α-VEGF axis. 11 As an upstream regulator of the angiogenic response, HIF-1α can increase angiogenesis by activating other pathways in addition to VEGF. There is a complex tandem between HIF-1α and bFGF, and HIF-1α-bFGF forms an autocrine loop under hypoxic conditions, suggesting the existence of an amplification pathway that mediates the survival of endothelial cells and neovascularization sprouting.…”

Section: Promoting Angiogenesismentioning

confidence: 99%

“…This activates the hypoxia‐induced pathway in the periosteum and stem cells in the bone marrow at the injury site, resulting in an increase in HIF‐1α expression, further acting on downstream target genes and upregulating the core regulator VEGF during angiogenesis 46 . A rat fracture model treated with intermittent hypoxia and found that VEGF expression in the fracture site was significantly increased compared with that in the control group at weeks 2 and 4, while platelet endothelial cell adhesion molecule‐1 (PECAM‐1; CD31), a vessel‐specific marker, was also specifically increased, suggesting that intermittent hypoxia promoted local vascular regeneration by upregulating the HIF‐1α‐VEGF axis 11 . As an upstream regulator of the angiogenic response, HIF‐1α can increase angiogenesis by activating other pathways in addition to VEGF.…”

Section: The Possible Mechanism By Which Hif‐1α Promotes Bone Regener...mentioning

confidence: 99%

See 2 more Smart Citations

Spatiotemporal correlation between HIF ‐1α and bone regeneration

et al. 2022

View full text Add to dashboard Cite

Hypoxia‐inducible factors (HIFs) are core regulators of the hypoxia response. HIF signaling is activated in the local physiological and pathological hypoxic environment, acting on downstream target genes to synthesize the corresponding proteins and regulate the hypoxic stress response. HIFs belong to the hypoxia‐activated transcription family and contain two heterodimeric transcription factors, HIF‐α and HIF‐β. Under hypoxia, the dimer formed by HIF‐α binding to HIF‐β translocates into the nucleus and binds to the hypoxia response element (HRE) to induce transcription of a series of genes. HIF‐1α plays an important role in innate bone development and acquired bone regeneration. HIF‐1α promotes bone regeneration mainly through the following two pathways: (1) By regulating angiogenesis‐osteoblast coupling to promote bone regeneration; and (2) by inducing metabolic reprogramming in osteoblasts, promoting cellular anaerobic glycolysis, ensuring the energy supply of osteoblasts under hypoxic conditions, and further promoting bone regeneration and repair. This article reviews recent basic research on HIF‐1α and its role in promoting osteogenesis, discusses the possible molecular mechanisms, introduces the hypoxia‐independent role of HIF‐1α and reviews the application prospects of HIF‐1α in tissue engineering.

show abstract

Section: The Possible Mechanism By Which Hif‐1α Promotes Bone Regener...mentioning

confidence: 90%

Section: Promoting Angiogenesismentioning

confidence: 99%

Section: The Possible Mechanism By Which Hif‐1α Promotes Bone Regener...mentioning

confidence: 99%

See 1 more Smart Citation

Spatiotemporal correlation between HIF ‐1α and bone regeneration

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Although a few studies report that chronic intermittent hypoxia in OSA brings a negative effect on bone formation, some other studies find that chronic intermittent hypoxia does no harm to the bone and it can even enhance bone fracture healing. 43 , 44 It is critical to define key characteristics of CIH protocol, including the exposure periods per day, the duration of hypoxic episodes and hypoxia levels. Severe/chronic CIH protocols tend to be pathogenic, while beneficial effects are more likely to result from modest/acute CIH exposures.…”

Section: Discussionmentioning

confidence: 99%

Orexin-A Reverse Bone Mass Loss Induced by Chronic Intermittent Hypoxia Through OX1R-Nrf2/HIF-1α Pathway

Gu¹,

Ru²,

Wang³

et al. 2022

DDDT

View full text Add to dashboard Cite

Background: Recent studies suggest that there is a potential connection between obstructive sleep apnea (OSA) and osteoporosis through dysregulation of bone metabolism. Orexin-A, a neuroprotective peptide secreted by the hypothalamus, is at a lower level in the plasma of OSA patients, which regulates appetite, energy expenditure and sleep-wake states. However, the protective effect of orexin-A on bone metabolism in OSA is unclear. Purpose: To investigate whether the activation of OX1R by orexin-A can reverse bone mass loss induced by chronic intermittent hypoxia (CIH). Methods: Mice were randomly divided into the normoxia group and CIH group. Within the CIH or normoxia groups, treatment groups were given a subcutaneous injection of either orexin-A or saline vehicle once every day for 4 weeks and then femurs were removed for micro-CT scans. Histology and immunohistochemical staining were performed to observe and calculate the changes in femurs as a result of hypoxia. Cell immunofluorescence and immunohistochemical staining were used to detect the expression of orexin receptors in MC3T3-E1 cells or in bones. CCK-8 assay, ALP assay kit and alizarin red staining were used to detect the viability, alkaline phosphatase (ALP) activity, and capacity of mineralization, respectively. The effect of orexin-A on osteogenic differentiation of MC3T3-E1 cells was evaluated using qRT-PCR, Western blot and cell staining. Results: CIH led to a decrease in the amount and density of trabecular bone, downregulated OCN expression while increasing osteoclast numbers in femurs and inhibited the expression of RUNX2, OSX, OPN and Nrf2 in MC3T3-E1 cells. Orexin-A treatment alleviated these CIH-induced effects by combining to OX1R. The level of HIF-1α was elevated both in CIH and orexin-A treatment groups. Conclusion: CIH environment inhibits osteogenesis and orexin-A can reverse bone mass loss induced by CIH through OX1R-Nrf2 /HIF-1α pathway.

show abstract

“…As a result, blood flow drops immediately, leading to regional hypoxia. However, in part, hypoxia is also involved in promoting fracture healing [ 13 ]. Therefore, hypoxia plays a particular role in bone homeostasis under physiological and pathological aspects, and exploring and clarifying the underlying mechanism is necessary.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Inducible Factors Signaling in Osteogenesis and Skeletal Repair

Qin

Liu²,

Yang³

et al. 2022

IJMS

View full text Add to dashboard Cite

Sufficient oxygen is required to maintain normal cellular and physiological function, such as a creature’s development, breeding, and homeostasis. Lately, some researchers have reported that both pathological hypoxia and environmental hypoxia might affect bone health. Adaptation to hypoxia is a pivotal cellular event in normal cell development and differentiation and in pathological settings such as ischemia. As central mediators of homeostasis, hypoxia-inducible transcription factors (HIFs) can allow cells to survive in a low-oxygen environment and are essential for the regulation of osteogenesis and skeletal repair. From this perspective, we summarized the role of HIF-1 and HIF-2 in signaling pathways implicated in bone development and skeletal repair and outlined the molecular mechanism of regulation of downstream growth factors and protein molecules such as VEGF, EPO, and so on. All of these present an opportunity for developing therapies for bone regeneration.

show abstract

Chronic Intermittent Hypobaric Hypoxia Enhances Bone Fracture Healing

Cited by 17 publications

References 65 publications

Spatiotemporal correlation between HIF ‐1α and bone regeneration

Spatiotemporal correlation between HIF ‐1α and bone regeneration

Orexin-A Reverse Bone Mass Loss Induced by Chronic Intermittent Hypoxia Through OX1R-Nrf2/HIF-1α Pathway

Hypoxia-Inducible Factors Signaling in Osteogenesis and Skeletal Repair

Contact Info

Product

Resources

About