Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects

Loots, Gabriela G.; Robling, Alexander G.; Chang, Jiun Chiun; Murugesh, Deepa K.; Bajwa, Jamila; Carlisle, Cameron; Manilay, Jennifer O.; Wong, Alice; Yellowley, Clare E.; Genetos, Damian C.

doi:10.1016/j.bone.2018.08.022

Cited by 33 publications

(41 citation statements)

References 51 publications

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“…29 Studies showed that loss of VHL significantly promoted angiogenesis via enhancing HIF-1α expression. 30 In our further WB results, the VHL gene was less expressed in the HP Mg group at three, six, and nine weeks postoperatively, and was lowest at the sixth week. In summary, combined with the results of all previous trials, we propose a mechanism hypothesis that magnesium promotes osteogenesis and calcification of distracted osteogenic new bone.…”

Section: Discussionmentioning

confidence: 59%

High-purity magnesium pin enhances bone consolidation in distraction osteogenesis model through activation of the VHL/HIF-1α/VEGF signaling

et al. 2020

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Distraction osteogenesis has widespread clinical use in the treatment of large bone defects. Nonetheless, the prolonged consolidation period carries the risk of complications. Magnesium-based materials have been shown to promote bone regeneration in fracture healing both in vitro and in vivo. Here, we investigated whether high-purity magnesium could enhance bone formation in distraction osteogenesis. High-purity magnesium pins were placed into the medullary cavity in the rat distraction osteogenesis model. Results showed that the bone volume/total tissue volume, bone mineral density, and mechanical properties of new callus were significantly higher in the high-purity magnesium group compared to stainless steel and control group (p < 0.01). Histological analyses confirmed improved bone consolidation and vascularization in high-purity magnesium group. Further, polymerase chain reaction-array investigation, Western blot, and immunohistochemical results found that vascular endothelial growth factor and hypoxia inducible factor-1α were highly expressed in the high-purity magnesium group, while Von Hippel–Lindau protein was the opposite (p < 0.01). In conclusion, high-purity magnesium implants have the potential to enhance angiogenesis and bone consolidation in the distraction osteogenesis application, and this process might be via the regulation of Von Hippel–Lindau/hypoxia inducible factor-1α/vascular endothelial growth factor signaling.

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Section: Discussionmentioning

confidence: 59%

High-purity magnesium pin enhances bone consolidation in distraction osteogenesis model through activation of the VHL/HIF-1α/VEGF signaling

et al. 2020

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“…Nevertheless, inappropriate HIF-1α signaling resulted in collagen overmodification and skeletal dysplasia (Stegen et al 2019), suggesting the complicated role of HIF-1α in endochondral osteogenesis. HIF-1α was considered to be required for osteoclast activation in postmenopausal osteoporosis (Miyauchi et al 2013; Loots et al 2018; Stegen et al 2018). However, the unique function of osteoclasts in condylar development was poorly understood.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α Mediates Osteoclast-Induced Mandibular Condyle Growth via AMPK Signaling

et al. 2020

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During the mandibular condylar growth, the absorption of calcified cartilage matrix induced by osteoclasts is crucial for the continuous endochondral osteogenesis. Meanwhile, recent studies showed that subchondral bone resided within the low-oxygen microenvironment, and our previous study revealed that hypoxia-inducible transcription factor 1α (HIF-1α) promoted osteoclastogenesis under hypoxia. However, whether HIF-1α regulates the function of osteoclasts in the mandibular condyle cartilage remains elusive. Our study indicated that severe deformity of the mandibular condyle was displayed in 10-wk-old osteoclast-specific HIF-1α conditional knockout (CKO) mice, accompanied by shortened length of condylar process and disorganized fibrocartilage. In 1-, 2-, and 4-wk-old CKO mice, the size of the hypertrophic layer and chondrocytic layer was significantly thickened. In the chondrocytic layer, chondrocytes were atrophied, showing a form of apoptosis in 4-wk-old CKO mice. Furthermore, an increase in the thickness of the fibrous and proliferating layer was observed in 10-wk-old CKO mice, as well as a significant decrease in that of the chondrocytic and hypertrophic chondrocyte layers. Interestingly, the articular surface of the condylar process abnormally presented a horizontal concave shape, and a disk-like acellular connective tissue appeared. In addition, genetic ablation of HIF-1α blunted cartilage matrix loss by subchondral osteoclast deficiency, resulting in a high subchondral bone mass phenotype, accompanied with a decreased number of blood vessels, alkaline phosphatase staining, and vascular endothelial growth factor (VEGF) expression. Mechanistically, the number of osteoclasts in the center of the condyle in CKO mice was significantly reduced by attenuated expression of adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling. These findings reveal a novel influence of HIF-1α function in osteoclasts on maintenance of osteoclast-induced resorption of calcified cartilage matrix via AMPK signaling, as well as subchondral bone formation through VEGF-dependent angiogenesis in bone marrow.

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“…After euthanasia, femora were stripped of soft‐tissue, fixed in 3.7% formaldehyde in phosphate‐buffered saline for 48 h at 4°C, then transferred to 70% ethanol in water and stored at 4°C; later, femora were scanned at 55 kVp, 145 mA, with 6 μm voxel size (Scanco Medical μCT 35, Brüttisellen, Switzerland) in the manner of Loots et al Tissue mineral density distribution (TMDD) within mid‐diaphyseal cortical bone from sham and Abx‐treated mice was obtained by distributing voxels into 100 evenly spaced bins (410–1,500 mg HA/cm 3 ). Mean calcium content (Ca MEAN ), peak calcium content (Ca PEAK ), and width at half‐maximum (Ca WIDTH ) were calculated in the manner of Borah et al Briefly, Ca MEAN reflects the average mineralization of the whole bone sample, Ca PEAK indicates the most frequently occurring calcium concentration, and Ca WIDTH is the width of the calcium distribution at its half peak height.…”

Section: Methodsmentioning

confidence: 99%

Sexually Dimorphic Influence of Neonatal Antibiotics on Bone

Pusceddu

Stokes

Wong

et al. 2019

Journal Orthopaedic Research

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The gut microbiome (GM) contributes to host development, metabolism, and disease. Perturbations in GM composition, elicited through chronic administration of oral antibiotics (Abx) or studied using germ‐free environments, alter bone mass, and microarchitecture. However, studies primarily involved chronic Abx exposure to adult mice prior to evaluating the skeletal phenotype. Children are more prone to infection with bacterial pathogens than adults and are thus treated more frequently with broad‐spectrum Abx; consequently, Abx treatment disproportionately occurs during periods of greatest skeletal plasticity to anabolic cues. Because early‐life exposures may exert long‐lasting effects on adult health, we hypothesized that acute Abx administration during a developmentally sensitive period would elicit lasting effects on the skeletal phenotype. To test this hypothesis, neonatal mice were treated with Abx (P7‐P23; oral gavage) or vehicle (water); GM composition, gut physiology, and bone structural and material properties were assessed in adulthood (8 weeks). We found sexually dimorphic effects of neonatal Abx administration on GM composition, gut barrier permeability, and the skeleton, indicating a negative role for neonatal Abx on bone mass and quality. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2122–2129, 2019

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Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects

Cited by 33 publications

References 51 publications

High-purity magnesium pin enhances bone consolidation in distraction osteogenesis model through activation of the VHL/HIF-1α/VEGF signaling

High-purity magnesium pin enhances bone consolidation in distraction osteogenesis model through activation of the VHL/HIF-1α/VEGF signaling

HIF-1α Mediates Osteoclast-Induced Mandibular Condyle Growth via AMPK Signaling

Sexually Dimorphic Influence of Neonatal Antibiotics on Bone

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