Uptake of ox-LDL by binding to LRP6 mediates oxidative stress-induced BMSCs senescence promoting obesity-related bone loss
Uptake of ox-LDL by binding to LRP6 mediates oxidative stress-induced BMSCs senescence promoting obesity-related bone loss
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DOI：
10.1016/j.cellsig.2024.111114
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发表时间：
2024-02-26
影响因子：
4.8
通讯作者：
Wang，Lei
中科院分区：
文献类型：
--
作者：
Meng，Senxiong;Wang，Zhuan;Wang，Lei
长期以来，肥胖一直被认为是高脂血症的主要原因。作为一种全身性疾病，肥胖对器官、组织和细胞的影响几乎都是负面的。然而，肥胖与骨质流失之间的关系最具争议。一方面，长期以来，肥胖一直被认为对骨骼有积极影响，因为骨骼上的机械负荷增加，有利于增加骨量以适应额外的体重。另一方面，肥胖相关的体内低密度脂蛋白（LDL）代谢氧化修饰导致骨髓微环境中氧化型低密度脂蛋白（ox-LDL）逐渐增加。我们报道了低密度脂蛋白受体相关蛋白6（LRP6）作为ox-LDL的受体并介导骨髓基质细胞（BMSC）对ox-LDL的摄取。我们检测到肥胖小鼠血清 ox-LDL 升高。我们发现LRP6摄取ox-LDL会导致BMSCs中细胞内活性氧（ROS）增加，N-乙酰基-L-半胱氨酸（NAC）减轻ox-LDL诱导的细胞衰老和成骨损伤。此外，LRP6 是 Wnt 信号传导的共同受体。我们发现 LRP6 优先与 ox-LDL 结合，而不是与 dickkopf 相关蛋白 1 (DKK1) 结合，两者均抑制 Wnt 信号传导并促进 BMSC 衰老。中胚层发育 LRP 伴侣 (MESD) 过表达抑制 ox-LDL 与 LRP6 的结合，减轻氧化应激和 BMSC 衰老，最终挽救骨表型。
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.