Mice with increased angiogenesis and osteogenesis due to conditional activation of HIF pathway in osteoblasts are protected from ovariectomy induced bone loss

Zhao, Qiang; Shen, Xing; Zhang, Wei; Zhu, Guochun; Qi, Jin; Deng, Lianfu

doi:10.1016/j.bone.2011.12.003

Cited by 92 publications

(67 citation statements)

References 32 publications

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“…Hence, for acute bone injuries, limited and transient activation of PHD/ HIF signaling may prove to be beneficial by enhancing blood vessel invasion and the recruitment of new osteoprogenitors, both of which are critical mediators for efficient and proper bone healing after fractures. Given these observations, it has been postulated that pan-PHD inhibitors could also be used for the treatment of chronic metabolic bone disorders such as osteoporosis (Zhao et al 2012). In support of this hypothesis, DMOG has been shown to increase trabecular bone and bone strength mediated by VEGF-induced angiogenesis; however, it should be noted that these experiments were performed on rats over a relatively short period of time (Liu et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin

et al. 2015

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The bone microenvironment is composed of niches that house cells across variable oxygen tensions. However, the contribution of oxygen gradients in regulating bone and blood homeostasis remains unknown. Here, we generated mice with either single or combined genetic inactivation of the critical oxygen-sensing prolyl hydroxylase (PHD) enzymes (PHD1-3) in osteoprogenitors. Hypoxia-inducible factor (HIF) activation associated with Phd2 and Phd3 inactivation drove bone accumulation by modulating osteoblastic/osteoclastic cross-talk through the direct regulation of osteoprotegerin (OPG). In contrast, combined inactivation of Phd1, Phd2, and Phd3 resulted in extreme HIF signaling, leading to polycythemia and excessive bone accumulation by overstimulating angiogenic-osteogenic coupling. We also demonstrate that genetic ablation of Phd2 and Phd3 was sufficient to protect ovariectomized mice against bone loss without disrupting hematopoietic homeostasis. Importantly, we identify OPG as a HIF target gene capable of directing osteoblast-mediated osteoclastogenesis to regulate bone homeostasis. Here, we show that coordinated activation of specific PHD isoforms fine-tunes the osteoblastic response to hypoxia, thereby directing two important aspects of bone physiology: cross-talk between osteoblasts and osteoclasts and angiogenic-osteogenic coupling.

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Section: Discussionmentioning

confidence: 99%

Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin

et al. 2015

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“…Liu et al found that in female mice in which the HIF-1 α gene in osteoblasts was conditionally knocked out, the trabecular number, volume, thickness, bone density, and some cytokines associated with osteogenesis and angiogenesis decreased significantly compared with wild-type mice 8 weeks after the mice were ovariectomised [89]. A similar investigation performed by Zhao et al showed that in female mice in which the HIF pathway in osteoblasts was activated via disruption of the HIF-degrading von Hippel-Lindau (VHL) protein, the bone structural and mechanical quality parameters did not change substantially after the mice were ovariectomised [48]. However, in the normal mice, the bone mineral density and mechanical strength decreased with deteriorated bone microarchitecture after the ovariectomy.…”

Section: Applications Of Hif Pathway In Bone Repair and Regenerationmentioning

confidence: 99%

The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

Fan

et al. 2014

BioMed Research International

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Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs). PHD inhibitors (PHIs) activate the HIF pathway by preventing degradation of HIF-α via inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF), are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.

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“…For example, osteoblast-derived VEGF initiated repair of small bone defects via angiogenesis and inflammation (Hu & Olsen 2016) and, along with Hif-1α and Hif-2α, VEGF was reduced in the distal femur of OVX mice (Zhao et al 2012). Further, VEGF was augmented at the tibial growth plate in juvenile mice with administration of 1α,25(OH) 2 D 3 (Lin et al 2002) and its variants were produced by low and high mechanical deformations in human osteoblasts (Faure et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone

Prisby

2017

Journal of Endocrinology

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Bone tissue is highly vascularized due to the various roles bone blood vessels play in bone and bone marrow function. For example, the vascular system is critical for bone development, maintenance and repair, and provides O2, nutrients, waste elimination, systemic hormones, and precursor cells for bone remodeling. Further, bone blood vessels serve as egress and ingress routes for blood and immune cells to and from the bone marrow. It is becoming increasingly clear that the vascular and skeletal systems are intimately linked in metabolic regulation and physiological and pathological processes. This review examines how agents such as mechanical loading, parathyroid hormone, estrogen, vitamin D and calcitonin, all considered anabolic for bone, have tremendous impacts on the bone vasculature. In fact, these agents influence bone blood vessels prior to impacting bone. Further, data reveal strong associations between vasodilator capacity of bone blood vessels and trabecular bone volume, and poor associations between estrogen status and uterine mass and trabecular bone volume. Additionally, this review highlights the importance of the bone microcirculation, particularly the vascular endothelium and NO-mediated signaling, in the regulation of bone blood flow, bone interstitial fluid flow and pressure, and the paracrine signaling of bone cells. Finally, the vascular endothelium as a mediator of bone health and disease is considered.

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Mice with increased angiogenesis and osteogenesis due to conditional activation of HIF pathway in osteoblasts are protected from ovariectomy induced bone loss

Cited by 92 publications

References 32 publications

Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin

Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin

The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone

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