Oxidized phospholipids are ligands for LRP6

Lei Wang, Yu Chai, Changjun Li, Haiyun Liu, Weiping Su, Xiaonan Liu, Bing Yu, Weiqi Lei, Bin Yu, Janet Crane, Xu Cao, Mei Wan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number22
JournalBone Research
Volume6
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Histology
  • Physiology

Cite this

Wang, L., Chai, Y., Li, C., Liu, H., Su, W., Liu, X., ... Wan, M. (2018). Oxidized phospholipids are ligands for LRP6. Bone Research, 6(1), [22]. https://doi.org/10.1038/s41413-018-0023-x