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.

Graphical Abstract

中文翻译：

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辅酶 Q10 通过调节 miR-130b-3p/PGC-1α 通路改善线粒体功能，预防高脂血症引起的骨质疏松症

在高脂血症引起的骨质疏松症中，骨髓间充质干细胞（BMSC）分化成的脂肪细胞多于成骨细胞，导致骨形成减少。阐明高脂血症对骨代谢的影响并寻找调节脂肪细胞-成骨细胞谱系分配的新药物至关重要。CoQ10 是线粒体呼吸链的限速辅酶，据报道可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，其对高脂血症引起的骨质疏松症的作用仍不清楚。在这里，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 BMSC中，血清脂质水平升高，骨形成相关标志物减少，而 CoQ10 可以逆转这种情况。此外，在 HFD 处理的ApoE ^−/−小鼠和 ox-LDL 处理的 BMSC 中，PGC-1α 蛋白表达降低，并伴有线粒体功能障碍、ATP 含量降低和活性氧 (ROS) 过度生成，这也可能被辅酶Q10。此外，体外 PGC-1α 敲低可促进 ROS 生成、BMSC 凋亡和成脂分化，同时减弱 BMSC 的成骨分化。从机制上讲，这表明在高脂血症条件下的骨质疏松症中，miR-130b-3p抑制剂治疗可增加PGC1-α蛋白的表达，从而改善线粒体功能。总的来说，CoQ10 可减轻ApoE ^−/−小鼠中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。可能的潜在机制可能涉及通过调节 miR-130b-3p/PGC-1α 通路来改善线粒体功能。

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