HIF signaling: A new propellant in bone regeneration

Bai, Hetian; Wang, Yue; Zhao, Yi; Chen, Xin; Xiao, Yu; Bao, Chongyun

doi:10.1016/j.bioadv.2022.212874

Cited by 14 publications

(12 citation statements)

References 134 publications

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“…Meanwhile, overexpressing of HIF-1α could also signi cantly upregulate osteogenesis-related mRNA and protein such as ALP, RUNX2, COL-1 and BMP2 in ADSCs. These results were consistent with the present research and suggested that HIF-1α was involved in the osteogenesis of ADSCs and plays a key role in this process (44,45).…”

Section: Discussionsupporting

confidence: 94%

HIF-1α promotes osteogenic regeneration of titanium implants by coupling angiogenesis and osteogenesis via HIF-1α/VEGF/AKT/mTOR signaling pathway

Song

Zhang

Chen

et al. 2023

Preprint

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Background: Stabilization and increased activity of hypoxia-inducible factor 1-α (HIF-1α) could directly increase cancellous bone formation and was playing an essential role in bone modeling and remodeling. However, whether an increase of HIF-1α in ADSCs promoted osteogenic differentiation and bone formation was not known. Results: In this study, ADSCs transfected with small interfering RNA and HIF-1α overexpression cDNA were established to investigate the proliferation, migration, adhesion, and osteogenic capacity in ADSCs, and angiogenic ability in HUVEC. Overexpression of HIF-1α could promote cell proliferation, migration, adhesive and osteogenic capacity of ADSCs and angiogenic ability of HUVEC. Western blotting showed that the protein levels of osteogenesis-related factors were upregulated when overexpression of HIF-1α. Furthermore, the influence of up-regulating HIF-1α in ADSCs sheets on osseointegration had evaluated using the SD rats implant model, in which the bone mass and osteoid mineralization speed were evaluated by radiological and histological analysis. The over-expression of HIF-1α in ADSCs enhanced osteogenic differentiation and osseointegration around implants. Whereas transfecting HIF-1α-silenced ADSCs attenuated the osteogenic and angiogenic capacity. Finally, to explore the mechanism underlying HIF-1α promoted osteogenesis and angiogenesis, Western blotting was measured to analyze the VEGF/AKT/mTOR signaling pathway. Conclusions: These data first demonstrated that up-regulation of HIF-1α in ADSCs significantly improved the osteogenic capacity and peri-implant bone formation via VEGF/AKT/mTOR signaling pathway. Our findings revealed that HIF-1α exerts a critical effect on promoting osseointegration by improving osteogenesis and angiogenesis via VEGF/AKT/mTOR signaling pathway, and hence offered the considerable therapeutic potential for modifying stem cells to enhance osseointegration.

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Section: Discussionsupporting

confidence: 94%

HIF-1α promotes osteogenic regeneration of titanium implants by coupling angiogenesis and osteogenesis via HIF-1α/VEGF/AKT/mTOR signaling pathway

Song

Zhang

Chen

et al. 2023

Preprint

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“…We found that both the levels of Hif-1α and Lonp1 were increased in retina or optic nerve tissues from the same aged groups. Hif-1α, a regulator of the cellular response to hypoxia, is involved in cell survival, differentiation, and maintenance of homeostasis during hypoxia-injured cells [ 45 , 46 ], which also activates a specific cell-recovery process. Hif-1α controls the expression of VEGF to promote angiogenesis [ 47 , 48 ] or activates damaged cells undergo apoptosis through BNIP3, NIX, and NOXA [ 49 , 50 ], and induces mitophagy activating NIPE/NIX-dependent pathway and mitochondrial biogenesis [ 51 , 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of Extracellular Vesicles in Optic Nerve Injury: Neuroprotection and Mitochondrial Homeostasis

Park

Shin

Duong

et al. 2022

Cells

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Stem cell therapies hold great promise as alternative treatments for incurable optic nerve disorders. Although mesenchymal stem cells exhibit various tissue regeneration and recovery capabilities that may serve as valuable therapies, the clinical applications remain limited. Thus, we investigated the utility of extracellular vesicles (EVs) from human placenta-derived mesenchymal stem cells (hPSCs) in this context. Hypoxically preconditioned hPSCs (HPPSCs) were prepared via short-term incubation under 2.2% O2 and 5.5% CO2. The EVs were then isolated. R28 cells (retinal precursor cells) were exposed to CoCl2 and treated with EVs for 24 h. Cell proliferation and regeneration were measured using a BrdU assay and immunoblotting; ATP quantification revealed the extent of the mitochondrial function. The proteome was determined via liquid chromatography-tandem mass spectroscopy. Differentially expressed proteins (DEPs) were detected and their interactions identified. HPPSC_EVs functions were explored using animal models of optic nerve compression. HPPSC_EVs restored cell proliferation and mitochondrial quality control in R28 cells damaged by CoCl2. We identified DEPs (p < 0.05) that aided recovery. The mitochondrial DEPs included LONP1; PARK7; VDAC1, 2, and 3; HSPD1; and HSPA9. EVs regulated the levels of mitophagic proteins in R28 cells injured by hypoxia; the protein levels did not increase in LONP1 knockdown cells. LONP1 is a key mediator of the mitophagy that restores mitochondrial function after hypoxia-induced optic nerve injury.

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“…HIF signaling is involved in the coordinated differentiation of osteoblasts and osteoclasts [ 46 , 47 , 48 ]. During orthodontic loading, pressure-induced local hypoxia contributes to the stabilization of HIF-1, up-regulates the expression of vascular endothelial growth factor and RANKL in osteoblasts, and promotes osteoclast differentiation [ 11 , 29 , 49 ]. RANKL from osteoblasts interacts with the osteoclast precursor RANK, promoting osteoclast activation, whereas OPG (osteoclast inhibitory factor or osteoprotegerin) inhibits osteoclast differentiation.…”

Section: The Hypoxic Microenvironment Of Bonementioning

confidence: 99%

“…Most of them are HIF-dependent. HIF also plays a major regulatory role in angiogenesis, which is important in tumor metastasis [ 11 , 29 , 65 ].…”

Section: The Hypoxic Microenvironment Of Bonementioning

confidence: 99%

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Construction of Bone Hypoxic Microenvironment Based on Bone-on-a-Chip Platforms

Zhao

Yang

et al. 2023

IJMS

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The normal physiological activities and functions of bone cells cannot be separated from the balance of the oxygenation level, and the physiological activities of bone cells are different under different oxygenation levels. At present, in vitro cell cultures are generally performed in a normoxic environment, and the partial pressure of oxygen of a conventional incubator is generally set at 141 mmHg (18.6%, close to the 20.1% oxygen in ambient air). This value is higher than the mean value of the oxygen partial pressure in human bone tissue. Additionally, the further away from the endosteal sinusoids, the lower the oxygen content. It follows that the construction of a hypoxic microenvironment is the key point of in vitro experimental investigation. However, current methods of cellular research cannot realize precise control of oxygenation levels at the microscale, and the development of microfluidic platforms can overcome the inherent limitations of these methods. In addition to discussing the characteristics of the hypoxic microenvironment in bone tissue, this review will discuss various methods of constructing oxygen gradients in vitro and measuring oxygen tension from the microscale based on microfluidic technology. This integration of advantages and disadvantages to perfect the experimental study will help us to study the physiological responses of cells under more physiological-relevant conditions and provide a new strategy for future research on various in vitro cell biomedicines.

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HIF signaling: A new propellant in bone regeneration

Cited by 14 publications

References 134 publications

HIF-1α promotes osteogenic regeneration of titanium implants by coupling angiogenesis and osteogenesis via HIF-1α/VEGF/AKT/mTOR signaling pathway

HIF-1α promotes osteogenic regeneration of titanium implants by coupling angiogenesis and osteogenesis via HIF-1α/VEGF/AKT/mTOR signaling pathway

The Role of Extracellular Vesicles in Optic Nerve Injury: Neuroprotection and Mitochondrial Homeostasis

Construction of Bone Hypoxic Microenvironment Based on Bone-on-a-Chip Platforms

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