The consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis. Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters. Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis.

高脂肪饮食（HFD）与骨质疏松症和脆性骨折风险增加有关。然而，HFD 诱发骨质疏松的具体机制尚不完全清楚。我们的研究表明，接触 HFD 会导致骨髓间充质干细胞 (BMSC) 过早衰老，降低其增殖和成骨能力，从而导致骨质疏松症。转录组和染色质可及性分析显示，HFD 喂养小鼠的 BMSC 中维生素 D 受体 (VDR) 结合序列的染色质可及性降低，VDR 信号传导减弱，表明 VDR 是 BMSC 衰老的关键调节因子。值得注意的是，对 HFD 喂养的小鼠施用 VDR 激活剂可挽救 BMSC 衰老，并显着改善成骨、骨量和其他骨参数。从机制上讲，VDR 激活通过降低细胞内活性氧 (ROS) 水平和保留线粒体功能来减少 BMSC 衰老。我们的研究结果不仅阐明了 HFD 诱导 BMSC 衰老和相关骨质疏松症的机制，而且还为通过靶向 VDR-超氧化物歧化酶 2 (SOD2)-ROS 轴来治疗 HFD 诱导的骨质疏松症提供了新见解。