Inhibition of JNK and activation of the AMPK-Nrf2 axis by corosolic acid suppress osteolysis and oxidative stress
Inhibition of JNK and activation of the AMPK-Nrf2 axis by corosolic acid suppress osteolysis and oxidative stress
复制标题
科罗索酸抑制 JNK 和激活 AMPK-Nrf2 轴可抑制骨质溶解和氧化应激
DOI：
10.1016/j.niox.2018.11.002
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Wang, Jinwu
中科院分区：
文献类型：
--
作者：
Peng, Mingzheng;Qiang, Lei;Wang, Jinwu
细胞内活性氧有助于RANKL诱导的破骨细胞生成和骨质溶解。核因子-红细胞2相关因子2（Nrf 2）是一种氧化还原敏感的转录因子，通过诱导抗氧化剂和细胞保护酶在细胞防御氧化应激中起关键作用。在本研究中，首次证明科罗索酸（CA）通过抑制p-JNK和激活p-AMPK抑制RANKL诱导的破骨细胞生成和羟基磷灰石吸收。同时，在CA治疗期间，p-65、p-38、Akt和GSK-3 β被部分抑制。破骨细胞生成相关基因NFATc 1、c-fos、cathepsin K和CTR也被CA下调。此外，CA处理的破骨细胞的细胞内氧化应激显着降低，Nrf 2易位到细胞核中，激活抗氧化剂，包括HO-1，NQO-1，和GCLC的CA。建立LPS诱导的小鼠颅骨骨溶解模型，进行体内研究。显微CT形态学分析显示，CA治疗恢复了LPS诱导的骨丢失和破骨细胞的形成。此外，在体内，LPS组p-p65和p-JNK被激活，而CA抑制p-p65和p-JNK。CA的治疗在其减弱LPS诱导的骨溶解的过程中也激活了p-AMPK。总之，CA通过抑制JNK和激活AMPK-Nrf 2轴来抑制破骨细胞生成和氧化应激，从而有效地防止LPS诱导的骨质溶解。
The intracellular reactive oxygen species contribute to RANKL-induced osteoclastogenesis and osteolysis. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a redox-sensitive transcription factor, is critical in the cellular defense against oxidative stress by induction of antioxidants and cytoprotective enzymes. In the current study, it was first demonstrated that RANKL-induced osteoclastogenesis and hydroxylapatite resorption were suppressed by Corosolic acid (CA) via inhibiting p-JNK and activating p-AMPK. Meanwhile, p-65, p-38, Akt, and GSK-3 beta were partly inhibited during the treatment of CA. Osteoclastogenesis related genes, including NFATc1, c-fos, cathepsin K, and CTR were down-regulated by CA as well. Furthermore, the intracellular oxidative stress of CA-treated osteoclasts was dramatically decreased and Nrf2 was translocated into the nucleus to activate antioxidants including HO-1, NQO-1, and GCLC by CA. The LPS-induced mice calvarial osteolysis model was established for the in vivo investigation. Micro-CT morphometric analysis revealed that the treatment of CA restored LPS-induced bone loss and formation of osteoclasts. Besides, p-p65 and p-JNK were activated in the LPS group but inhibited by CA in vivo. The treatment of CA also activated p-AMPK during its attenuating LPS-induced osteolysis. Conclusively, CA effectively protects against LPS-induced osteolysis by suppressing osteoclastogenesis and oxidative stress through the inhibition of the JNK and activation of the AMPK-Nrf2 axis.