在高脂血症引起的骨质疏松症中,骨髓间充质干细胞(BMSCs)分化为更多的脂肪细胞比成骨细胞,导致骨形成减少。阐明高脂血症对骨代谢的影响并寻求调节脂肪细胞-成骨细胞谱系分配的新药物至关重要。辅酶Q10,线粒体呼吸链的限速辅酶,据报道,通过充当线粒体抗氧化剂来减少氧化应激和脂质过氧化。然而,其对高脂血症所致骨质疏松症的影响尚不清楚.这里,我们通过使用高脂饮食(HFD)处理的ApoE-/-小鼠或氧化低密度脂蛋白(ox-LDL)处理的BMSCs,分析了CoQ10对高脂血症诱导的骨质疏松症的治疗机制.在HFD处理的ApoE-/-小鼠和ox-LDL处理的BMSCs中,血脂水平升高,骨形成相关标志物降低,这可以被CoQ10逆转。此外,在HFD处理的ApoE-/-小鼠和ox-LDL处理的BMSCs中PGC-1α蛋白表达降低,伴有线粒体功能障碍,降低ATP含量和活性氧(ROS)的过度产生,这也可以被CoQ10拮抗。此外,PGC-1α敲低体外促进ROS生成,BMSC凋亡,和脂肪分化,同时减弱BMSCs的成骨分化。机械上,提示miR-130b-3p抑制剂治疗高脂血症骨质疏松可增加PGC1-α蛋白的表达,从而改善线粒体功能。总的来说,CoQ10缓解ApoE-/-小鼠高脂血症诱导的骨质疏松症,并调节脂肪细胞-成骨细胞谱系分配。其潜在机制可能涉及通过调节miR-130b-3p/PGC-1α通路改善线粒体功能。
In hyperlipidemia-induced osteoporosis, bone marrow mesenchymal stem cells (BMSCs) differentiate into more adipocytes than osteoblasts, leading to decreased bone formation. It is vital to elucidate the effects of hyperlipidemia on bone metabolism and seek new agents that regulate adipocyte-osteoblast lineage allocation.
CoQ10, a rate-limiting coenzyme of the mitochondrial respiratory chain, has been reported to decrease oxidative stress and lipid peroxidation by functioning as a mitochondrial antioxidant. However, its effect on hyperlipidemia-induced osteoporosis remains unknown. Here, we analyzed the therapeutic mechanisms of
CoQ10 on hyperlipidemia-induced osteoporosis by using high-fat diet (HFD)-treated ApoE-/- mice or oxidized low-density lipoprotein (ox-LDL)-treated BMSCs. The serum lipid levels were elevated and bone formation-related markers were decreased in HFD-treated ApoE-/- mice and ox-LDL-treated BMSCs, which could be reversed by
CoQ10. Additionally, PGC-1α protein expression was decreased in HFD-treated ApoE-/- mice and ox-LDL-treated BMSCs, accompanied by mitochondrial dysfunction, decreased ATP content and overgeneration of reactive oxygen species (ROS), which could also be antagonized by
CoQ10. Furthermore, PGC-1α knockdown in vitro promoted ROS generation, BMSC apoptosis, and adipogenic differentiation while attenuating osteogenic differentiation in BMSCs. Mechanistically, it suggested that the expression of PGC1-α protein was increased with miR-130b-3p inhibitor treatment in osteoporosis under hyperlipidemia conditions to improve mitochondrial function. Collectively,
CoQ10 alleviates hyperlipidemia-induced osteoporosis in ApoE-/- mice and regulates adipocyte-osteoblast lineage allocation. The possible underlying mechanism may involve the improvement of mitochondrial function by modulating the miR-130b-3p/PGC-1α pathway.