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Stéphanie Fabre1,2, Morgane Bourmaud1, Guillaume Mabilleau3

  • 1INSERM U1132 Bioscar Université de Paris Cité Paris France.

JBMR Plus
|June 7, 2023
PubMed
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The LRP5 Val667Met variant is linked to reduced bone mineral density and impaired bone quality in early-onset osteoporosis. This study investigated its impact on bone and eye health, revealing abnormalities in mice.

Area of Science:

  • Genetics and Molecular Biology
  • Bone and Mineral Metabolism
  • Ophthalmology

Background:

  • Early-onset osteoporosis (EOOP) is associated with genetic factors, including the LRP5 gene, crucial for the Wnt signaling pathway.
  • The LRP5 p.Val667Met (V667M) variant, identified through GWAS, is linked to low bone mineral density (BMD) and increased fracture risk.
  • Previous studies suggested a connection between LRP5 variants and both bone and ocular abnormalities, but the specific impact of V667M required further investigation.

Purpose of the Study:

  • To evaluate the bone and ocular effects of the LRP5 V667M variant.
  • To assess the impact of the V667M variant on bone microarchitecture, cellular function, and matrix composition.
  • To investigate potential ocular abnormalities associated with the V667M variant in both human patients and a mouse model.
Keywords:
Lrp5Wntbone densitycollagenefracture

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Main Methods:

  • Recruitment of 11 patients with LRP5 V667M or other loss-of-function variants.
  • Generation of an Lrp5 V667M mutated mouse model for preclinical evaluation.
  • Assessment of bone mineral density (BMD), bone microarchitecture (HR-pQCT), osteoblast differentiation, mineralization, gene expression (Osx, Col1, osteocalcin), bone matrix composition (hydroxyproline/proline ratio), and retinal vascularization.

Main Results:

  • Patients exhibited low lumbar and hip BMD Z-scores and altered bone microarchitecture.
  • Lrp5 V667M osteoblasts showed reduced differentiation, alkaline phosphatase activity, and mineralization in vitro.
  • Lrp5 V667M mice displayed decreased femur and lumbar spine BMD, altered bone matrix composition (lower hydroxyproline/proline ratio), and a trend toward reduced stiffness, along with higher retinal vascular tortuosity.

Conclusions:

  • The LRP5 V667M variant is associated with diminished BMD and compromised bone matrix quality.
  • The study identified ocular vascular abnormalities, specifically retinal vessel tortuosity, in the Lrp5 V667M mouse model.
  • These findings highlight the dual role of LRP5 in skeletal integrity and retinal vascular development, underscoring the V667M variant's pathological significance.