Uptake of ox-LDL by binding to LRP6 mediates oxidative stress-induced BMSCs senescence promoting obesity-related bone loss

Cell Signal. 2024 May:117:111114. doi: 10.1016/j.cellsig.2024.111114. Epub 2024 Feb 20.

Abstract

Obesity has long been thought to be a main cause of hyperlipidemia. As a systemic disease, the impact of obesity on organs, tissues and cells is almost entirely negative. However, the relationship between obesity and bone loss is highly controversial. On the one hand, obesity has long been thought to have a positive effect on bone due to increased mechanical loading on the skeleton, conducive to increasing bone mass to accommodate the extra weight. On the other hand, obesity-related metabolic oxidative modification of low-density lipoprotein (LDL) in vivo causes a gradual increase of oxidized LDL (ox-LDL) in the bone marrow microenvironment. We have reported that low-density lipoprotein receptor-related protein 6 (LRP6) acts as a receptor of ox-LDL and mediates the bone marrow stromal cells (BMSCs) uptake of ox-LDL. We detected elevated serum ox-LDL in obese mice. We found that ox-LDL uptake by LRP6 led to an increase of intracellular reactive oxygen species (ROS) in BMSCs, and N-acetyl-L-cysteine (NAC) alleviated the cellular senescence and impairment of osteogenesis induced by ox-LDL. Moreover, LRP6 is a co-receptor of Wnt signaling. We found that LRP6 preferentially binds to ox-LDL rather than dickkopf-related protein 1 (DKK1), both inhibiting Wnt signaling and promoting BMSCs senescence. Mesoderm development LRP chaperone (MESD) overexpression inhibits ox-LDL binding to LRP6, attenuating oxidative stress and BMSCs senescence, eventually rescuing bone phenotype.

Keywords: BMSCs; Bone loss; LRP6; Oxidized LDL; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow* / metabolism
  • Carrier Proteins / metabolism
  • Lipoproteins, LDL / metabolism
  • Lipoproteins, LDL / pharmacology
  • Low Density Lipoprotein Receptor-Related Protein-6* / metabolism
  • Mice
  • Obesity / complications
  • Oxidative Stress

Substances

  • Carrier Proteins
  • Lipoproteins, LDL
  • Low Density Lipoprotein Receptor-Related Protein-6
  • oxidized low density lipoprotein
  • Lrp6 protein, mouse