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Regulation of the bone vascular network is sexually dimorphic

Regulation of the bone vascular network is sexually dimorphic
Regulation of the bone vascular network is sexually dimorphic
Osteoblast (OB) lineage cells are an important source of vascular endothelial growth factor (VEGF), which is critical for bone growth and repair. During bone development, pubertal differences in males and females exist, but little is known about whether VEGF signalling contributes to skeletal sexual dimorphism. We have found that in mice, conditional disruption of VEGF in osteocalcin expressing cells (OcnVEGFKO) exerts a divergent influence on morphological, cellular, and whole bone properties between sexes. Furthermore, we describe an underlying sexual divergence in VEGF signalling in OB cultures in vitro independent of circulating sex‐hormones. High‐resolution synchrotron computed tomography and backscattered scanning electron microscopy revealed, in males, extensive unmineralised osteoid encasing enlarged blood vessel canals and osteocyte lacunae in cortical bone following VEGF deletion, which contributed to increased porosity. VEGF was deleted in male and female long bone‐derived OBs (OBVEGKO) in vitro and Raman spectroscopic analyses of mineral and matrix repertoires highlighted differences between male and female OBVEGFKO cells, with increased immature phosphate species prevalent in male OBVEGFKO cultures versus WT. Further sexual dimorphism was observed in bone marrow endothelial cell gene expression in vitro following VEGF deletion and in sclerostin protein expression, which was increased in male OcnVEGFKO bones versus WT. The impact of altered OB matrix composition following VEGF deletion on whole bone geometry was assessed between sexes, although significant differences between OcnVEGFKO and WT were identified only in females. Our results suggest that bone‐derived VEGF regulates matrix mineralisation and vascularisation distinctly in males and females which results in divergent physical bone traits.
0884-0431
2117-2132
Goring, Alice
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Sharma, Aikta
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Javaheri, Behazad
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Smith, Rosanna
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Kanczler, Janos
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Boyde, Alan
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Hesse, Eric
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Mahajan, Sumeet
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Olsen, Bjorn
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Pitsillides, Andrew
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Schneider, Philipp
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Oreffo, Richard
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Clarkin, Claire
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Goring, Alice
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Sharma, Aikta
de245946-e5d9-434a-9c08-07ab87ae7691
Javaheri, Behazad
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Smith, Rosanna
1fe5586f-92e9-4658-bd55-cd3eaa176b66
Kanczler, Janos
eb8db9ff-a038-475f-9030-48eef2b0559c
Boyde, Alan
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Hesse, Eric
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Mahajan, Sumeet
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Olsen, Bjorn
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Pitsillides, Andrew
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Schneider, Philipp
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Oreffo, Richard
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Clarkin, Claire
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Goring, Alice, Sharma, Aikta, Javaheri, Behazad, Smith, Rosanna, Kanczler, Janos, Boyde, Alan, Hesse, Eric, Mahajan, Sumeet, Olsen, Bjorn, Pitsillides, Andrew, Schneider, Philipp, Oreffo, Richard and Clarkin, Claire (2019) Regulation of the bone vascular network is sexually dimorphic. Journal of Bone and Mineral Research, 34 (11), 2117-2132. (doi:10.1002/jbmr.3825).

Record type: Article

Abstract

Osteoblast (OB) lineage cells are an important source of vascular endothelial growth factor (VEGF), which is critical for bone growth and repair. During bone development, pubertal differences in males and females exist, but little is known about whether VEGF signalling contributes to skeletal sexual dimorphism. We have found that in mice, conditional disruption of VEGF in osteocalcin expressing cells (OcnVEGFKO) exerts a divergent influence on morphological, cellular, and whole bone properties between sexes. Furthermore, we describe an underlying sexual divergence in VEGF signalling in OB cultures in vitro independent of circulating sex‐hormones. High‐resolution synchrotron computed tomography and backscattered scanning electron microscopy revealed, in males, extensive unmineralised osteoid encasing enlarged blood vessel canals and osteocyte lacunae in cortical bone following VEGF deletion, which contributed to increased porosity. VEGF was deleted in male and female long bone‐derived OBs (OBVEGKO) in vitro and Raman spectroscopic analyses of mineral and matrix repertoires highlighted differences between male and female OBVEGFKO cells, with increased immature phosphate species prevalent in male OBVEGFKO cultures versus WT. Further sexual dimorphism was observed in bone marrow endothelial cell gene expression in vitro following VEGF deletion and in sclerostin protein expression, which was increased in male OcnVEGFKO bones versus WT. The impact of altered OB matrix composition following VEGF deletion on whole bone geometry was assessed between sexes, although significant differences between OcnVEGFKO and WT were identified only in females. Our results suggest that bone‐derived VEGF regulates matrix mineralisation and vascularisation distinctly in males and females which results in divergent physical bone traits.

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Goring et al 2019 Journal of Bone and Mineral Research - Version of Record
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Accepted/In Press date: 24 June 2019
e-pub ahead of print date: 3 July 2019
Published date: 1 November 2019

Identifiers

Local EPrints ID: 432290
URI: http://eprints.soton.ac.uk/id/eprint/432290
ISSN: 0884-0431
PURE UUID: e85e9893-6d38-4605-9b4d-ccee45c2cbe0
ORCID for Aikta Sharma: ORCID iD orcid.org/0000-0002-5449-358X
ORCID for Janos Kanczler: ORCID iD orcid.org/0000-0001-7249-0414
ORCID for Sumeet Mahajan: ORCID iD orcid.org/0000-0001-8923-6666
ORCID for Philipp Schneider: ORCID iD orcid.org/0000-0001-7499-3576
ORCID for Richard Oreffo: ORCID iD orcid.org/0000-0001-5995-6726

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Date deposited: 08 Jul 2019 16:30
Last modified: 18 Feb 2021 17:32

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Contributors

Author: Alice Goring
Author: Aikta Sharma ORCID iD
Author: Behazad Javaheri
Author: Rosanna Smith
Author: Janos Kanczler ORCID iD
Author: Alan Boyde
Author: Eric Hesse
Author: Sumeet Mahajan ORCID iD
Author: Bjorn Olsen
Author: Andrew Pitsillides
Author: Richard Oreffo ORCID iD
Author: Claire Clarkin

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