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

Obesity has long been thought to a main cause of hyperlipidemia. As a systemic disease, the impact of obesity on organs, tissues and cells are almost all negative. However, the relationship between obesity and bone loss is most controversial. On the one hand, obesity has long been thought to a positive effect on bone due to increased mechanical loading on the skeleton, conducive to increase bone mass to accommodate the extra weight. On the other hand, obesity-related metabolic oxidative modification of low-density lipoprotein (LDL) in vivo caused the gradual increase of oxidized LDL (ox-LDL) in the bone marrow microenvironment. We had reported that low-density lipoprotein receptor-related protein 6 (LRP6) acts as receptor of ox-LDL and mediated 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 leaded to the increase of intracellular reactive oxygen species (ROS) in BMSCs, N-acetyl-L-cysteine (NAC) alleviating the cellular senescence and impairment of osteogenesis induced by ox-LDL. Moreover, LRP6 is a co-receptor of Wnt signaling. We found LRP6 preferentially bound to ox-LDL rather dickkopf-related protein 1 (DKK1), both inhibiting Wnt signaling and promoting BMSCs senescence. Mesoderm development LRP chaperone (MESD) overexpression inhibition of ox-LDL binding to LRP6, attenuating oxidative stress and BMSCs senescence, eventually rescuing bone phenotype.