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  2. 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

  • Redox Biol. 2020 Jan;28:101309. doi: 10.1016/j.redox.2019.101309.
Xuewu Sun 1 Ziang Xie 1 Bin Hu 2 Boya Zhang 3 Yan Ma 1 Xin Pan 1 Hai Huang 1 Jiying Wang 1 Xiangde Zhao 1 Zhiwei Jie 1 Peihua Shi 4 Zhijun Chen 5
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Musculoskeletal System Degeneration, Regeneration Translational Research of Zhejiang Province, Hangzhou, China.
  • 2 Department of Orthopedic Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, China.
  • 3 Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
  • 4 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Musculoskeletal System Degeneration, Regeneration Translational Research of Zhejiang Province, Hangzhou, China. Electronic address: peihua_shi@zju.edu.cn.
  • 5 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Musculoskeletal System Degeneration, Regeneration Translational Research of Zhejiang Province, Hangzhou, China. Electronic address: 21418223@zju.edu.cn.
Abstract

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-β. Here, we found that RTA-408 could suppress STING expression, but that it does not affect Ifnb1 expression. RANKL-induced degradation of IκBα and the nuclear translocation of P65 was suppressed by RTA-408. Although this compound was not found to influence STING-IFN-β 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-κB 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-κB 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.

Keywords

Nrf2; Osteoclastogenesis; RTA-408; STING.

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