Oxidized phospholipids are ligands for LRP6

Abstract

Low-density lipoprotein receptor–related protein 6 (LRP6) is a co-receptor for Wnt signaling and can be recruited by multiple growth factors/hormones to their receptors facilitating intracellular signaling activation. The ligands that bind directly to LRP6 have not been identified. Here, we report that bioactive oxidized phospholipids (oxPLs) are native ligands of LRP6, but not the closely related LRP5. oxPLs are products of lipid oxidation involving in pathological conditions such as hyperlipidemia, atherosclerosis, and inflammation. We found that cell surface LRP6 in bone marrow mesenchymal stromal cells (MSCs) decreased rapidly in response to increased oxPLs in marrow microenvironment. LRP6 directly bound and mediated the uptake of oxPLs by MSCs. oxPL-LRP6 binding induced LRP6 endocytosis through a clathrin-mediated pathway, decreasing responses of MSCs to osteogenic factors and diminishing osteoblast differentiation ability. Thus, LRP6 functions as a receptor and molecular target of oxPLs for their adverse effect on MSCs, revealing a potential mechanism underlying atherosclerosis-associated bone loss.

Bone loss: revealing a molecular cause of ‘numb’ stem cells

A constituent of oxidized ‘bad cholesterol’ blocks essential signaling processes leading to pathogenic bone loss. LRP6 is a crucial receptor involved in multiple physiological processes, including bone loss; however, direct pathogenic modulators of the receptor have yet to be elucidated. Now, John Hopkins University School of Medicine’s Mei Wan, with a US and Chinese research team, has discovered that oxPL, a byproduct of the oxidization of cholesterol carrier LDL, binds directly to LRP6 and causes its removal from the surface of bone marrow stem cells. As a result, these stem cells are unable to sense the external signaling molecules that drive bone growth. oxPLs are products of diseases such as hyperlipidemia and atherosclerosis, and this paper helps to reveal their pathogenesis and offers potential targets for therapeutic interventions.

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Funding

Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)(DK083350)