Controlling hypoxia-inducible factor-2α is critical for maintaining bone homeostasis in mice

Lee, Sun Young; Park, Ka Hyon; Yu, Hyung-Gu; Kook, Eunbyul; Song, Won-Hyun; Lee, Gyuseok; Koh, Jeong‐Tae; Shin, Hong‐In; Choi, Je‐Yong; Huh, Yun Hyun; Ryu, Je‐Hwang

doi:10.1038/s41413-019-0054-y

Cited by 43 publications

(114 citation statements)

References 71 publications

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“…14,15 Reduced HIF-2α activity promotes endochondral and intramembranous ossification and bone repair. 16,17 We thus hypothesized that HIF-2α gain-of-function in our patients led to persistent hypoxic signaling, incomplete mesenchymal development, reduced bony development of the spine and skull base, and CM1 with associated sacral abnormalities. 10 The present study evaluates 8 patients with EPAS1 gain-offunction syndrome for the presence of posterior fossa and spinal malformations.…”

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confidence: 95%

Neuraxial dysraphism in EPAS1- associated syndrome due to improper mesenchymal transition

et al. 2020

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ObjectiveTo investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in EPAS1 gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia.MethodsPatients referred to our institution for evaluation of new, recurrent, and/or metastatic paragangliomas/pheochromocytoma were confirmed for EPAS1 gain-of-function syndrome by identification of the EPAS1 gain-of-function mutation in resected tumors and/or circulating leukocytes. The posterior fossa, its contents, and the spine were evaluated retrospectively on available MRI and CT images of the head and neck performed for tumor staging and restaging. The transgenic mouse model underwent Microfil vascular perfusion and subsequent intact ex vivo 14T MRI and micro-CT as well as gross dissection, histology, and immunohistochemistry to assess the role of EPAS1 in identified malformations.ResultsAll 8 patients with EPAS1 gain-of-function syndrome demonstrated incidental posterior fossa malformations—one Dandy-Walker variant and 7 Chiari malformations without syringomyelia. These findings were not associated with a small posterior fossa; rather, the posterior fossa volume exceeded that of its neural contents. Seven of 8 patients demonstrated spinal dysraphism; 4 of 8 demonstrated abnormal vertebral segmentation. The mouse model similarly demonstrated features of neuraxial dysraphism, including cervical myelomeningocele and spinal dysraphism, and cerebellar tonsil displacement through the foramen magnum. Histology and immunohistochemistry demonstrated incomplete mesenchymal transition in the mutant but not the control mouse.ConclusionsThis study characterized posterior fossa and spinal malformations seen in EPAS1 gain-of-function syndrome and suggests that gain-of-function mutation in HIF-2α results in improper mesenchymal transition.

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confidence: 95%

Neuraxial dysraphism in EPAS1- associated syndrome due to improper mesenchymal transition

et al. 2020

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“…However, it has recently been reported that HIF-2 is a negative regulator of osteoblastogenesis (S. Y. Lee et al, 2019;Merceron et al, 2019). Deficiency of HIF-2 increases bone mass through promoting osteoblast differentiation and inhibiting osteoclast differentiation (Merceron et al, 2019).…”

Section: Osteoblastsmentioning

confidence: 99%

“…Similarly, HIF-2α deficiency is shown to promote osteoblast differentiation and increase bone formation in mice (S. Y. Lee et al, 2019). S. Y.…”

Section: Osteoblastsmentioning

confidence: 99%

“Take My Bone Away?” Hypoxia and bone: A narrative review

Hannah

McFadden

McNeilly

et al. 2020

Journal Cellular Physiology

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To maintain normal cellular and physiological function, sufficient oxygen is required. Recently, evidence has suggested that hypoxia, either pathological or environmental, may influence bone health. It appears that bone cells are distinctly responsive to hypoxic stimuli; for better or worse, this is still yet to be elucidated. Hypoxia has been shown to offer potentially therapeutic effects for bone by inducing an osteogenic-angiogenic response, although, others have noted excessive osteoclastic bone resorption instead. Much evidence suggests that the hypoxic-inducible pathway is integral in mediating the changes in bone metabolism. Furthermore, many factors associated with hypoxia including changes in energy metabolism, acid-base balance and the increased generation of reactive oxygen species, are known to influence bone metabolism. This review aims to examine some of the putative mechanisms responsible for hypoxic-induced alterations of bone metabolism, with regard to osteoclasts and osteoblasts, both positive and negative.

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“…HIF-2α deficiency in mice enhances bone mass, in part by increasing osteoclastogenesis. HIF-2 stimulates RANKL-induced osteoclastogenesis via regulation of osteoclast Traf6 and also increases RANKL expression in osteoprogenitor cells [38]. This could mean that in 3D culture in vivo, possible effects of FG-4592 to drive a HIF-mediated increase in RANKL expression by other bone-resident cells could have large effects on osteoclast differentiation and activity within the local bone microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that this is due to changes in the RANKL:OPG ratio, although our data regarding effects on OPG:RANKL expression was variable and inconclusive (data not shown). This could be because expression of both RANKL [35][36][37][38] and OPG [5,19] can be induced by HIF activation and / or PHD enzyme inhibition. Full transcriptional investigation of this complex experimental system would facilitate identification of all contributing factors.…”

Section: Discussionmentioning

confidence: 99%

Osteoblast-osteoclast co-culture amplifies inhibitory effects of FG-4592 on osteoclast formation and reduces bone resorption activity

Hulley

Papadimitriou-Olivgeri

Knowles

2019

Preprint

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The link between bone and blood vessels is regulated by hypoxia and the hypoxia-inducible transcription factor, HIF, which drives both osteogenesis and angiogenesis. The recent clinical approval of PHD enzyme inhibitors, which stabilise HIF protein, introduces the potential for a new clinical strategy to treat osteolytic conditions such as osteoporosis, osteonecrosis and skeletal fracture and non-union. However, bone-resorbing osteoclasts also play a central role in bone remodelling and pathological osteolysis and HIF promotes osteoclast activation and bone loss in vitro. It is therefore likely that the final outcome of PHD enzyme inhibition in vivo would be mediated by a balance between increased bone formation and increased bone resorption. It is essential that we improve our understanding of the effects of HIF on osteoclast formation and function, and consider the potential contribution of inhibitory interactions with other musculoskeletal cells.The PHD enzyme inhibitor FG-4592 stabilised HIF protein and stimulated osteoclast-mediated bone resorption, but inhibited differentiation of human CD14+ monocytes into osteoclasts. Formation of osteoclasts in a more physiologically relevant 3D collagen gel did not affect the sensitivity of osteoclastogenesis to FG-4592, but increased sensitivity to reduced concentrations of RANKL. Coculture with osteoblasts amplified inhibition of osteoclastogenesis by FG-4592, whether the osteoblasts were proliferating, differentiating or in the presence of exogenous M-CSF and RANKL. Osteoblast co-culture dampened the ability of high concentrations of FG-4592 to increase bone resorption.This data provides support for the therapeutic use of PHD enzyme inhibitors to improve bone formation and/or reduce bone loss for treatment of osteolytic pathologies, and indicates that FG-4592 might also act to inhibit the formation and activity of the osteoclasts that drive osteolysis.

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Controlling hypoxia-inducible factor-2α is critical for maintaining bone homeostasis in mice

Cited by 43 publications

References 71 publications

Neuraxial dysraphism in EPAS1- associated syndrome due to improper mesenchymal transition

Neuraxial dysraphism in EPAS1- associated syndrome due to improper mesenchymal transition

“Take My Bone Away?” Hypoxia and bone: A narrative review

Osteoblast-osteoclast co-culture amplifies inhibitory effects of FG-4592 on osteoclast formation and reduces bone resorption activity

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