The Nrf2 activator RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling
The Nrf2 activator RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling
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Nrf2 激活剂 RTA-408 通过抑制 STING 依赖性 NF-κb 信号传导来减弱破骨细胞生成
DOI：
10.1016/j.redox.2019.101309
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发表时间：
2020-01-01
期刊：
影响因子：
11.4
通讯作者：
Chen, Zhijun
中科院分区：
文献类型：
--
作者：
Sun, Xuewu;Xie, Ziang;Chen, Zhijun
ROS产生和破骨细胞生成的失调参与了骨质疏松症的发展。为了找到治疗这种疾病的新的和有效的靶点，重要的是要探索潜在的机制。在我们的研究中，我们首先测试了Nrf 2激活剂RTA-408对破骨细胞生成的作用，RTA-408是一种新型合成三萜类化合物，正在临床研究中用于许多疾病。我们发现，它可以抑制破骨细胞分化和骨吸收的时间和剂量依赖性的方式。此外，RTA-408增强了Nrf 2的表达和活性，并显著抑制了RANKL诱导的活性氧（ROS）产生。Nrf 2调节STING表达，STING诱导IFN-β的产生。在这里，我们发现RTA-408可以抑制STING表达，但它不影响Ifnb 1表达。RTA-408可抑制RANKL诱导的I κ B α降解和P65核转位。尽管未发现该化合物影响STING-IFN-β信号传导，但它通过抑制STING和E3遍在蛋白连接酶TRAF 6之间的相互作用来抑制RANKL诱导的STING的K63遍在蛋白化。此外，腺病毒介导的STING过表达挽救了RTA-408对NF-κ B信号传导和破骨细胞生成的抑制作用。体内实验表明，该化合物可通过抑制破骨细胞生成有效减轻卵巢切除术（OVX）诱导的C57 BL/6小鼠骨丢失。总的来说，我们表明RTA-408通过抑制TRAF 6向STING的募集来抑制NF-κ B信号传导，此外还减弱了体内破骨细胞生成和OVX诱导的骨丢失，这表明它可能是未来治疗骨质疏松症的有希望的候选物。
The dysregulation of ROS production and osteoclastogenesis is involved in the progress of osteoporosis. To identify novel and effective targets to treat this disease, it is important to explore the underlying mechanisms. In our study, we firstly tested the effect of the Nrf2 activator RTA-408, a novel synthetic triterpenoid under clinical investigation for many diseases, on osteoclastogenesis. We found that it could inhibit osteoclast differentiation and bone resorption in a time- and dose-dependent manner. Further, RTA-408 enhanced the expression and activity of Nrf2 and significantly suppressed RANKL-induced reactive oxygen species (ROS) production. Nrf2 regulates the STING expression and STING induces the production of IFN-beta. Here, we found that RTA-408 could suppress STING expression, but that it does not affect Ifnb1 expression. RANKL-induced degradation of I kappa B alpha and the nuclear translocation of P65 was suppressed by RTA-408. Although this compound was not found to influence STING-IFN-beta signaling, it suppressed the RANKL-induced K63-ubiquitination of STING via inhibiting the interaction between STING and the E3 ubiquitin ligase TRAF6. Further, adenovirus-mediated STING overexpression rescued the suppressive effect of RTA-408 on NF-kappa B signaling and osteoclastogenesis. In vivo experiments showed that this compound could effectively attenuate ovariectomy (OVX)-induced bone loss in C57BL/6 mice by inhibiting osteoclastogenesis. Collectively, we show that RTA-408 inhibits NF-kappa B signaling by suppressing the recruitment of TRAF6 to STING, in addition to attenuating osteoclastogenesis and OVX-induced bone loss in vivo, suggesting that it could be a promising candidate for treating osteoporosis in the future.