Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway.
Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway.
复制标题
双氢青蒿素通过线粒体依赖性细胞凋亡途径减弱脂多糖诱导的破骨细胞生成和骨质流失。
DOI：
10.1038/cddis.2016.69
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发表时间：
2016-03-31
影响因子：
9
通讯作者：
Dong S
中科院分区：
文献类型：
--
作者：
Dou C;Ding N;Xing J;Zhao C;Kang F;Hou T;Quan H;Chen Y;Dai Q;Luo F;Xu J;Dong S
双氢青蒿素（DHA）是一种广泛使用的抗疟疾药物，分离自植物青蒿。近年来的研究表明，DHA具有抗肿瘤作用，其机制是通过产生活性氧（ROS）。本文报道了DHA对脂多糖（LPS）诱导的破骨细胞（OC）分化、融合和骨吸收活性的抑制作用。细胞内活性氧检测结果显示，DHA可显著增加LPS诱导的破骨细胞生成过程中活性氧的积累。此外，细胞凋亡也增加DHA处理。我们发现DHA激活的caspase-3在LPS诱导的破骨细胞生成过程中增加Bax/Bcl-2比值。同时，凋亡诱导因子（AIF）的易位和细胞色素c从线粒体释放到细胞质中，表明ROS介导的线粒体功能障碍是至关重要的DHA诱导的细胞凋亡在LPS诱导的破骨细胞生成。体内研究表明，DHA治疗降低了OC数量，防止了骨丢失，挽救了骨微结构，并恢复了LPS诱导的骨丢失小鼠模型的骨强度。总之，我们的研究结果表明，DHA通过ROS积累和DHA依赖性凋亡途径诱导破骨细胞凋亡，从而保护免受LPS诱导的骨丢失。因此，DHA可能被认为是治疗炎性骨丢失的新的治疗候选物。
Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss.