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RANKL, but Not R-Spondins, Is Involved in Vascular Smooth Muscle Cell Calcification through LGR4 Interaction.

Sara Fernández-Villabrille1,2, Julia Martín-Vírgala1,2, Beatriz Martín-Carro1,2

  • 1Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain.

International Journal of Molecular Sciences
|June 19, 2024
PubMed
Summary
This summary is machine-generated.

Vascular calcification is linked to bone loss. The study reveals Receptor Activator of Nuclear Factor Kappa B ligand (RANKL) interacting with Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) drives vascular calcification by promoting osteogenic differentiation in smooth muscle cells.

Keywords:
LGR4R-spondinsRANKLphosphorusvascular calcification

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Physiology

Background:

  • Vascular calcification poses a global health challenge, often correlating with bone loss.
  • The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system is crucial for bone metabolism and implicated in vascular calcification.
  • Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a RANKL receptor, is involved in bone remodeling and potentially vascular calcification, interacting with R-spondins (RSPOs).

Purpose of the Study:

  • To investigate the role of the RANKL/LGR4 axis in vascular calcification.
  • To explore the impact of high phosphate and parathyroid hormone (PTH) on vascular calcification and the RANKL/LGR4 system.
  • To assess the expression of the RANK/RANKL/OPG system and LGR4 ligands in human vascular tissue with calcification.

Main Methods:

  • Studies in rats with chronic renal failure on varying phosphorus diets and PTH levels to induce aortic calcification.
  • In vitro experiments with cultured vascular smooth muscle cells (VSMCs) exposed to different phosphate and PTH concentrations.
  • Investigation of soluble RANKL effects on VSMCs and the role of LGR4 via gene silencing.
  • Gene expression analysis of the RANK/RANKL/OPG system and LGR4 ligands in human epigastric arteries from kidney transplant recipients.

Main Results:

  • Increased aortic calcification in rats correlated with elevated systolic blood pressure, upregulated Lgr4 and Rankl, and downregulated Opg gene expression.
  • In vitro, elevated phosphate increased VSMC calcium content, Rankl, and Lgr4 expression while decreasing Opg; high PTH exacerbated these effects.
  • Soluble RANKL induced VSMC calcification, partly mediated by LGR4, and human arteries with calcification showed higher RANKL gene expression. RSPOs had minimal impact.

Conclusions:

  • RANKL, acting through its receptor LGR4, promotes osteogenic differentiation in VSMCs, contributing to vascular calcification via a novel mechanism.
  • The RANKL/LGR4 pathway is a significant factor in vascular calcification, particularly under conditions of high phosphate and elevated PTH.
  • Targeting the RANKL/LGR4 interaction may offer a therapeutic strategy for vascular calcification, independent of the classical RANK-RANKL pathway.