Hypoxia-inducible factor 2α is a negative regulator of osteoblastogenesis and bone mass accrual

Merceron, Christophe; Ranganathan, Kavitha; Wang, Elizabeth; Tata, Zachary; Makkapati, Shreya; Khan, Mohd Parvez; Mangiavini, Laura; Yao, Qing; Castellini, Laura; Lévi, Benjamin; Giaccia, Amato J.; Schipani, Ernestina

doi:10.1038/s41413-019-0045-z

Cited by 42 publications

(59 citation statements)

References 44 publications

(81 reference statements)

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“…Mechanistically, hypoxia has been shown to supress the RANKL decoy receptor, osteoprotegrin (OPG), preventing RANK-induced osteoclast formation and activity (Shirakura et al, 2010;Xian et al, 2016), although this has not been consistently demonstrated (Hulley et al, 2017;Kang et al, 2017;S. Y. Lee et al, 2019;Merceron et al, 2019;Shao et al, 2015;Wu et al, 2015). It is difficult to ascertain this inconsistency, but it may be explained by experimental variations of F I G U R E 1 HIF pathway activation.…”

Section: Osteoclastsmentioning

confidence: 99%

“…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%

“…The increase in osteoclast numbers following intermittent hypoxic exposure may also be related to increases in reactive oxygen species which may account for the increased differentiation is some studies (ROS: discussed later). Mechanistically, hypoxia has been shown to supress the RANKL decoy receptor, osteoprotegrin (OPG), preventing RANK‐induced osteoclast formation and activity (Shirakura et al, 2010; Xian et al, 2016), although this has not been consistently demonstrated (Hulley et al, 2017; Kang et al, 2017; S. Y. Lee et al, 2019; Merceron et al, 2019; Shao et al, 2015; Wu et al, 2015). It is difficult to ascertain this inconsistency, but it may be explained by experimental variations of HIF‐induction (hypoxia or gene editing), cell lines or single cell line work opposed to coculture or in vivo.…”

Section: Hypoxia and Bonementioning

confidence: 99%

“…Initial research identified that loss of HIF‐2 in both osteoprogenitors and osteoblasts did not impact osteoblast activity or number (Shomento et al, 2010; Wu et al, 2015). 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: Hif‐2: Too Good To Be True?mentioning

confidence: 99%

“…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). HIF‐2's impairment of osteoblastogenesis is partly regulated through Sox9—a negative regulator of osteoblast differentiation (Merceron et al, 2019; Zhou et al, 2006).…”

Section: Hif‐2: Too Good To Be True?mentioning

confidence: 99%

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“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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Section: Osteoclastsmentioning

confidence: 99%

Section: Osteoblastsmentioning

confidence: 99%

Section: Hypoxia and Bonementioning

confidence: 99%

Section: Hif‐2: Too Good To Be True?mentioning

confidence: 99%

Section: Hif‐2: Too Good To Be True?mentioning

confidence: 99%

See 3 more Smart Citations

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

Hannah

McFadden

McNeilly

et al. 2020

Journal Cellular Physiology

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Degradation‐Resistant Hypoxia Inducible Factor‐2α in Murine Osteocytes Promotes a High Bone Mass Phenotype

et al. 2023

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Molecular oxygen levels vary during development and disease. Adaptations to decreased oxygen bioavailability (hypoxia) are mediated by hypoxia‐inducible factor (HIF) transcription factors. HIFs are composed of an oxygen‐dependent α subunit (HIF‐α), of which there are two transcriptionally active isoforms (HIF‐1α and HIF‐2α), and a constitutively expressed β subunit (HIFβ). Under normoxic conditions, HIF‐α is hydroxylated via prolyl hydroxylase domain (PHD) proteins and targeted for degradation via Von Hippel‐Lindau (VHL). Under hypoxic conditions, hydroxylation via PHD is inhibited, allowing for HIF‐α stabilization and induction of target transcriptional changes. Our previous studies showed that Vhl deletion in osteocytes ( Dmp1‐cre; Vhl f/f ) resulted in HIF‐α stabilization and generation of a high bone mass (HBM) phenotype. The skeletal impact of HIF‐1α accumulation has been well characterized; however, the unique skeletal impacts of HIF‐2α remain understudied. Because osteocytes orchestrate skeletal development and homeostasis, we investigated the role of osteocytic HIF‐α isoforms in driving HBM phenotypes via osteocyte‐specific loss‐of‐function and gain‐of‐function HIF‐1α and HIF‐2α mutations in C57BL/6 female mice. Deletion of Hif1a or Hif2a in osteocytes showed no effect on skeletal microarchitecture. Constitutively stable, degradation‐resistant HIF‐2α (HIF‐2α cDR), but not HIF‐1α cDR, generated dramatic increases in bone mass, enhanced osteoclast activity, and expansion of metaphyseal marrow stromal tissue at the expense of hematopoietic tissue. Our studies reveal a novel influence of osteocytic HIF‐2α in driving HBM phenotypes that can potentially be harnessed pharmacologically to improve bone mass and reduce fracture risk. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Hypoxia‐Inducible Factor‐2α Signaling in the Skeletal System

2023

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Hypoxia‐inducible factors (HIFs) are oxygen‐dependent heterodimeric transcription factors that mediate molecular responses to reductions in cellular oxygen (hypoxia). HIF signaling involves stable HIF‐β subunits and labile, oxygen‐sensitive HIF‐α subunits. Under hypoxic conditions, the HIF‐α subunit is stabilized, complexes with nucleus‐confined HIF‐β subunit, and transcriptionally regulates hypoxia‐adaptive genes. Transcriptional responses to hypoxia include altered energy metabolism, angiogenesis, erythropoiesis, and cell fate. Three isoforms of HIF‐α—HIF‐1α, HIF‐2α, and HIF‐3α—are found in diverse cell types. HIF‐1α and HIF‐2α serve as transcriptional activators, whereas HIF‐3α restricts HIF‐1α and HIF‐2α. The structure and isoform‐specific functions of HIF‐1α in mediating molecular responses to hypoxia are well established across a wide range of cell and tissue types. The contributions of HIF‐2α to hypoxic adaptation are often unconsidered if not outrightly attributed to HIF‐1α. This review establishes what is currently known about the diverse roles of HIF‐2α in mediating the hypoxic response in skeletal tissues, with specific focus on development and maintenance of skeletal fitness. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Hypoxia-inducible factor 2α is a negative regulator of osteoblastogenesis and bone mass accrual

Cited by 42 publications

References 44 publications

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

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

Degradation‐Resistant Hypoxia Inducible Factor‐2α in Murine Osteocytes Promotes a High Bone Mass Phenotype

Hypoxia‐Inducible Factor‐2α Signaling in the Skeletal System

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