Gao Yijie, Zhou Rui, Lin Xixi, Liu Zhijuan, Su Yuangang, Lian Haoyu, Lin Bin, Ding Xiaofei, Liao Shijie, Li Xiangde, Zhao Jinmin, Xu Jiake, Xu Ren, Liu Qian, Song Fangming
Guangxi Key Laboratory of Regenerative Medicine, Orthopaedics Trauma and Hand Surgery, the First Affiliated Hospital of Guangxi Medical University, 22 Shuangyong Road, Nanning, 530000, China.
Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed By the Province and Ministry, Guangxi Medical University, Nanning, 530000, China.
J Transl Med. 2025 Jul 18;23(1):805. doi: 10.1186/s12967-025-06708-8.
Osteoporosis is a skeletal condition caused by an excess of osteoclasts, resulting in an imbalance in bone metabolism. Sinensetin (SIN), one of the main ingredients in citrus fruits, provides a variety of pharmacological properties, like antioxidant, but its effects on osteoporosis remains unknown. Herein, we explored at how SIN affected RANKL-induced osteoclastogenesis and ovariectomy (OVX)-induced osteoporotic mice. Our research found that SIN, without compromising cell viability, inhibited RANKL-mediated osteoclastogenesis and the NFATc1 signaling pathway in a concentration-dependent manner. Further, RNA sequencing analysis suggested that the molecular mechanism of SIN inhibitory effect on osteoclasts is related to the cytoskeleton reorganization. The results indicated that SIN prevents the cytoskeleton reorganization of preosteoclasts via the c-Src-mediated PI3K/PAK4/AKT signaling axis. Meanwhile, SIN enhanced the expression of phosphorylation and activity of AMP-activated protein kinase (AMPK) in response to RANKL. Further, SIN targets AMPK to reduce intracellular Reactive oxygen species (ROS) levels, thereby blocking c-Src activation. Finally, we verified that SIN inhibits osteoclast activity, thus preventing OVX-induced bone loss. These findings suggest that SIN serves as an AMPK activator that abrogates RANKL-induced osteoclastogenesis and OVX-induced bone loss via hindering cytoskeleton reorganization.
骨质疏松症是一种由破骨细胞过多引起的骨骼疾病，导致骨代谢失衡。橙皮素（SIN）是柑橘类水果中的主要成分之一，具有多种药理特性，如抗氧化作用，但其对骨质疏松症的影响尚不清楚。在此，我们探讨了SIN如何影响RANKL诱导的破骨细胞生成和卵巢切除（OVX）诱导的骨质疏松小鼠。我们的研究发现，SIN在不影响细胞活力的情况下，以浓度依赖性方式抑制RANKL介导的破骨细胞生成和NFATc1信号通路。此外，RNA测序分析表明，SIN对破骨细胞的抑制作用的分子机制与细胞骨架重组有关。结果表明，SIN通过c-Src介导的PI3K/PAK4/AKT信号轴阻止前破骨细胞的细胞骨架重组。同时，SIN增强了对RANKL反应时AMP激活蛋白激酶（AMPK）的磷酸化表达和活性。此外，SIN靶向AMPK以降低细胞内活性氧（ROS）水平，从而阻断c-Src激活。最后，我们证实SIN抑制破骨细胞活性，从而预防OVX诱导的骨质流失。这些发现表明，SIN作为一种AMPK激活剂，通过阻碍细胞骨架重组消除RANKL诱导的破骨细胞生成和OVX诱导的骨质流失。
