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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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Sex differences in murine bone matrix maturation modulate osteoblast-endothelial interactions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月2日

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  • Aikta Sharma,
  • Roger J. H. Emery,
  • Andrew A. Pitsillides,
  • Claire E. Clarkin

摘要

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.