2. Academic Validation
  3. Virtual screening identified natural Keap1-Nrf2 PPI inhibitor alleviates inflammatory osteoporosis through Nrf2-mir214-Traf3 axis

Virtual screening identified natural Keap1-Nrf2 PPI inhibitor alleviates inflammatory osteoporosis through Nrf2-mir214-Traf3 axis

  • Free Radic Biol Med. 2021 Aug 1;171:365-378. doi: 10.1016/j.freeradbiomed.2021.05.020.
Jianqiao Hong 1,  Zhongli Shi 1,  Congsun Li 1,  Xiaoxiao Ji 1,  Sihao Li 1,  Yazhou Chen 1,  Guangyao Jiang 1,  Mingmin Shi 1,  Wei Wang 1,  Yongxing Zhang 2,  Bin Hu 3,  Shigui Yan 4
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Orthopedic Research Institute of Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province Hangzhou, Zhejiang, China.
  • 2 Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Orthopedic Research Institute of Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province Hangzhou, Zhejiang, China. Electronic address: phenixzyx@zju.edu.cn.
  • 3 Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Orthopedic Research Institute of Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province Hangzhou, Zhejiang, China. Electronic address: 11618327@zju.edu.cn.
  • 4 Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Orthopedic Research Institute of Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province Hangzhou, Zhejiang, China. Electronic address: zrjwsj@zju.edu.cn.
PMID: 34000381 DOI: 10.1016/j.freeradbiomed.2021.05.020
Abstract

Overactive osteoclastogenesis is involved in the inflammatory bone loss and could be target for therapy. Here, we applied transcription factor enrichment analysis using public inflammatory osteolysis datasets and identified Nrf2 as the potential therapeutic target. Additionally, in-silico screening was performed to dig out Nrf2-Keap1 PPI inhibitor and Forsythoside-β was found to be the best-performing PHG compound. We firstly tested the effect of Forsythoside-β in inflammatory osteoporosis models and found it was able to attenuate the bone loss by inhibiting osteoclastogenesis and activating Nrf2-signaling in vivo. Forsythoside-β was capable to suppress the differentiation of osteoclast in time and dose-dependent manners in vitro. Further, Forsythoside-β could inhibit the production of Reactive Oxygen Species and induce Nrf2 nuclear-translocation by interrupting Nrf2-Keap1 PPI. Recently, Nrf2 was identified as the epigenetic regulator modulating levels of miRNA in various diseases. We discovered that Forsythoside-β could suppress the expression of mir-214-3p, one of most variable miRNAs during osteoclastogenesis. To clarify the undermining mechanism, by utilizing chip-seq dataset, we found that Nrf2 could bind to promoter of mir-214-3p and further regulate this miRNA. Collectively, Forsythoside-β was able to prevent bone loss through Nrf2-mir-214-3p-Traf3 axis, which could be a promising candidate for treating inflammatory bone loss in the future.

Keywords

Inflammatory osteoporosis; Molecular docking; Nrf2; Traf3; miRNA.

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