Sex differences in murine bone matrix maturation modulate osteoblast-endothelial interactions.
5 affiliations
- 1Department of Mechanical Engineering, University College London, London, WC1E 7JE, UK. [email protected].
- 2School of Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK. [email protected].
- 3The Hamlyn Centre for Robotic Surgery, Imperial College London, London, SW7 2AZ, UK.
- 4Department of Comparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, UK.
- 5School of Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK. [email protected].
Abstract
Background
Bone formation during skeletal growth and repair is divergently modulated by osteoblast-derived vascular endothelial growth factor (VEGF), which contributes to the sexual dimorphism of the bone vasculature. While the extracellular matrix (ECM) provides structural and instructive cues to developing vasculature, whether the osteoblast-derived matrix contributes to this dimorphism remains unclear.Methods
Primary osteoblasts from the long bones of neonatal female and male C57BL/6J mice were cultured under basal or osteogenic conditions for compositional ECM analysis by Raman spectroscopy. Primary murine bone marrow-derived endothelial cells (BMECs) were seeded onto established osteoblast layers and maintained in heterotypic cocultures to assess contact-mediated effects of osteoblast ECM on BMEC survival and expansion. Osteoblast-derived conditioned media (CM) were used to evaluate soluble-factor contributions, with VEGF-A concentration quantified by ELISA.Results
Raman spectroscopy of monocultured osteoblasts revealed sexually dimorphic ECM signatures independent of cellular growth profiles. Female matrices were enriched with type I collagen-associated proline and hydroxyproline and octacalcium phosphate, consistent with a matrix-dominant signature. Male matrices exhibited lower levels of collagen-associated components and instead adopted a more mineral-mature profile, reflected by CAP accumulation and an elevated mineral/matrix ratio. In heterotypic cocultures, BMEC numbers were 1.39-fold higher with male than female osteoblasts. CM treatment of BMECs did not recapitulate these effects despite higher VEGF-A release from male osteoblasts.Conclusions
Sex differences in osteoblast-derived ECM are linked to divergent, contact-dependent modulation of BMEC behaviour. These findings indicate that intrinsic sex differences in osteoblast matrix maturation may contribute to sex-specific regulation of the skeletal vascular niche. Defining how osteoblast-derived ECM regulates skeletal vascularisation may reveal targets for selectively modulating pathological skeletal angiogenesis in women and men.
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BibTeX
@article{sharma2026differences,
title = {{Sex differences in murine bone matrix maturation modulate osteoblast-endothelial interactions.}},
author = {Aikta Sharma and Roger J H Emery and Andrew A Pitsillides and Claire E Clarkin},
journal = {Biology of sex differences},
year = {2026},
month = aug,
doi = {10.1186/s13293-026-00960-3},
url = {https://europepmc.org/article/MED/42958447},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sex differences in murine bone matrix maturation modulate osteoblast-endothelial interactions.
AU - Aikta Sharma
AU - Roger J H Emery
AU - Andrew A Pitsillides
AU - Claire E Clarkin
PY - 2026
DA - 2026/08/02
JO - Biology of sex differences
DO - 10.1186/s13293-026-00960-3
UR - https://europepmc.org/article/MED/42958447
AB - Background Bone formation during skeletal growth and repair is divergently modulated by osteoblast-derived vascular endothelial growth factor (VEGF), which contributes to the sexual dimorphism of the bone vasculature. While the extracellular matrix (ECM) provides structural and instructive cues to developing vasculature, whether the osteoblast-derived matrix contributes to this dimorphism remains unclear.Methods Primary osteoblasts from the long bones of neonatal female and male C57BL/6J mice were cultured under basal or osteogenic conditions for compositional ECM analysis by Raman spectroscopy. Primary murine bone marrow-derived endothelial cells (BMECs) were seeded onto established osteoblast layers and maintained in heterotypic cocultures to assess contact-mediated effects of osteoblast ECM on BMEC survival and expansion. Osteoblast-derived conditioned media (CM) were used to evaluate soluble-factor contributions, with VEGF-A concentration quantified by ELISA.Results Raman spectroscopy of monocultured osteoblasts revealed sexually dimorphic ECM signatures independent of cellular growth profiles. Female matrices were enriched with type I collagen-associated proline and hydroxyproline and octacalcium phosphate, consistent with a matrix-dominant signature. Male matrices exhibited lower levels of collagen-associated components and instead adopted a more mineral-mature profile, reflected by CAP accumulation and an elevated mineral/matrix ratio. In heterotypic cocultures, BMEC numbers were 1.39-fold higher with male than female osteoblasts. CM treatment of BMECs did not recapitulate these effects despite higher VEGF-A release from male osteoblasts.Conclusions Sex differences in osteoblast-derived ECM are linked to divergent, contact-dependent modulation of BMEC behaviour. These findings indicate that intrinsic sex differences in osteoblast matrix maturation may contribute to sex-specific regulation of the skeletal vascular niche. Defining how osteoblast-derived ECM regulates skeletal vascularisation may reveal targets for selectively modulating pathological skeletal angiogenesis in women and men.
SN - 2042-6410
ER -