Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; International Institute for Translational Research of Traditional Chinese Medicine of Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
Biomed Pharmacother. 2021 May;137:111382. doi: 10.1016/j.biopha.2021.111382. Epub 2021 Feb 23.
Accumulating studies have indicated that reactive oxygen species (ROS) may be implicated into the destructive pathological events of rheumatoid arthritis (RA). As an effective antioxidant, artesunate (ARS) was reported to exert antiarthritic effects. However, whether ARS attenuates the bone erosion during RA progression by regulating ROS production remains to be defined. To address this problem, the inhibitive effects of ARS on osteoclastogenesis were observed in vitro. Mechanically, ARS significantly inhibited the NFATc1 signaling accompanied by markedly suppressing ROS production, which was abnormally enhanced during the pathological process of bone erosion. In addition, ARS may function as a potent ROS scavenger and significantly elevate the expression of HO-1 and NQO1 by activating Nrf2. Moreover, p62 accumulation induced by ARS was responsible for the activation of Nrf2, while the knockdown of p62 in osteoclast precursor cells diminished the suppressive effect of ARS on ROS production during osteoclastogenesis. Consistently, we also demonstrated that ARS effectively suppressed ROS production, leading to the inhibition of arthritic bone destruction by activating antioxidant enzyme and Nrf2/p62 signaling in the knee and ankle tissues of CIA rats. Collectively, our data offer the convincing evidence that ARS may inhibit osteoclastogenesis and ameliorate arthritic bone erosion through suppressing the generation of ROS via activating the p62/Nrf2 signaling.
越来越多的研究表明，活性氧（ROS）可能参与类风湿关节炎（RA）的破坏性病理事件。青蒿琥酯（ARS）作为一种有效的抗氧化剂，据报道具有抗关节炎作用。然而，ARS 是否通过调节 ROS 产生来减轻 RA 进展过程中的骨质侵蚀仍有待确定。为了解决这个问题，我们在体外观察了 ARS 对破骨细胞形成的抑制作用。从机制上讲，ARS 显著抑制 NFATc1 信号转导，同时显著抑制 ROS 产生，而在骨质侵蚀的病理过程中，ROS 产生异常增强。此外，ARS 可能作为一种有效的 ROS 清除剂，通过激活 Nrf2 显著增加 HO-1 和 NQO1 的表达。此外，ARS 诱导的 p62 积累负责激活 Nrf2，而在破骨细胞前体细胞中敲低 p62 则减弱了 ARS 对破骨细胞形成过程中 ROS 产生的抑制作用。一致地，我们还表明，ARS 通过激活抗氧化酶和 Nrf2/p62 信号通路有效抑制 ROS 产生，从而抑制 CIA 大鼠膝关节和踝关节组织中的关节炎性骨破坏。综上所述，我们的数据提供了令人信服的证据，表明 ARS 可能通过激活 p62/Nrf2 信号通路抑制 ROS 的产生来抑制破骨细胞形成并改善关节炎性骨质侵蚀。
