Osteocytic oxygen sensing: Distinct impacts of VHL and HIF-2alpha on bone integrity

Mendoza, Sarah V.; Wells, Kristina V.; Murugesh, Deepa K.; Hum, Nicholas R.; Sebastian, Aimy; Gorman, Bria M.; Wong, Alice; Osipov, Benjamin; Christiansen, Blaine A.; Loots, Gabriela G.; Robling, Alexander G.; Yellowley, Clare E.; Genetos, Damian C.

doi:10.1016/j.bone.2024.117339

Title: Osteocytic oxygen sensing: Distinct impacts of VHL and HIF-2alpha on bone integrity

Journal Article · 26 November 2024 · Bone

DOI: https://doi.org/10.1016/j.bone.2024.117339 · OSTI ID:2510519

Mendoza, Sarah V. ^[1]; Wells, Kristina V. ^[1]; Murugesh, Deepa K. ^[2]; Hum, Nicholas R. ^[2]; Sebastian, Aimy ^[2]; Gorman, Bria M. ^[2]; Wong, Alice ^[1]; Osipov, Benjamin ^[3]; Christiansen, Blaine A. ^[3]; Loots, Gabriela G. ^[4]; Robling, Alexander G. ^[5]; Yellowley, Clare E. ^[1]; Genetos, Damian C. ^[1]

Univ. of California, Davis, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Univ. of California Davis Medical Center, Sacramento, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); Univ. of California Davis Medical Center, Sacramento, CA (United States)
Indiana University School of Medicine, Indianapolis IN (United States)

Skeletal fracture resistance emerges from multiple components of bone structure like microarchitecture, matrix mineralization, and organization. These characteristics are engendered via mechanisms like the hypoxia-inducible factors (HIF) pathway, involving two paralogs, HIF-1α and HIF-2α. Under normoxia, HIF-α is targeted for degradation via von-Hippel Lindau (VHL); hypoxia enables HIF-α stabilization and induction of target genes. We previously showed that osteocytic Vhl deletion or expression of degradation-resistant HIF-2α cDR female mice each produced high bone mass, whereas degradation-resistant osteocytic HIF-1α produced no overt phenotype. We report within that Vhl cKO increased bone strength, while HIF-2α cDR displayed markedly reduced bone strength below Cre-negative controls. This suggests that VHL and HIF-2α drive distinct responses that promote disparate effects on bone strength. Both Vhl deletion or HIF-2α accumulation generated two discrete bone morphologies: an outer lamellar cortex and a woven, poorly mineralized endocortex that imparted dramatically different functional outcomes. Our studies reveal novel influence of osteocytic HIF-2α signaling on collagen matrix organization, mineralization, and bone strength.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 2510519

Report Number(s):: LLNL-JRNL--2001928

Journal Information:: Bone, Journal Name: Bone Vol. 192; ISSN 8756-3282

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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