Oxidized phospholipids are ligands for LRP6.

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Medicine

Background:

• Low-density lipoprotein receptor-related protein 6 (LRP6) acts as a Wnt signaling co-receptor, crucial for intracellular signaling activation.
• The direct ligands for LRP6 have remained unidentified, limiting understanding of its regulatory mechanisms.

Purpose of the Study:

• To identify the native ligands that directly bind to LRP6.
• To investigate the functional consequences of ligand binding to LRP6 in mesenchymal stromal cells (MSCs).

Main Methods:

• Ligand binding assays to identify native LRP6 ligands.
• Cell surface expression analysis of LRP6 in MSCs under varying conditions.
• Investigation of oxPL uptake and endocytosis pathways mediated by LRP6.
• Assessment of MSC response to osteogenic factors and osteoblast differentiation capacity.

Main Results:

• Bioactive oxidized phospholipids (oxPLs) were identified as native ligands for LRP6, distinct from LRP5.
• Increased oxPL levels in the marrow microenvironment led to rapid decreases in cell surface LRP6 on MSCs.
• LRP6 mediated the direct binding and uptake of oxPLs by MSCs via clathrin-mediated endocytosis.
• oxPL-LRP6 interaction diminished MSC responsiveness to osteogenic factors and impaired osteoblast differentiation.

Conclusions:

• LRP6 functions as a direct receptor for oxPLs, mediating their detrimental effects on MSCs.
• This oxPL-LRP6 pathway represents a potential mechanism contributing to bone loss associated with atherosclerosis.
• Targeting the oxPL-LRP6 interaction may offer therapeutic strategies for atherosclerosis-related bone pathologies.