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J Bone Miner Res. 2019 Jul 3. doi: 10.1002/jbmr.3825. [Epub ahead of print]

Regulation of the bone vascular network is sexually dimorphic.

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School of Biological Sciences, Highfield Campus, University of Southampton, SO17 1BJ, Southampton.
Department of Comparative Biomedical Sciences, The Royal Veterinary College, NW1 0TU, London.
Bone and Joint Research Group, Centre for Human Development, Stem Cell and Regeneration, Human Development and Health, Institute of Developmental Sciences, University of Southampton, Tremona Road, SO16 6YD, Southampton.
Dental Physical Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Mile End campus, E1 4NS, London.
Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma-, Hand- and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
IfLS, Department of Chemistry, University of Southampton, SO17 1BJ, Southampton.
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, 02115, USA.
Faculty of Engineering and the Environment, Highfield Campus, University of Southampton, SO17 1BJ, Southampton.


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. This article is protected by copyright. All rights reserved.


Bone QCT/microCT; Genetic animal models; Matrix mineralisation; Osteoblasts; Preclinical Studies


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