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Updated: Nov 5, 2025
Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
Virtual screening identified natural Keap1-Nrf2 PPI inhibitor alleviates inflammatory osteoporosis through
Jianqiao Hong1, Zhongli Shi1, Congsun Li1
1Department 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.
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.
Insights
Forsythoside-β prevents inflammatory bone loss by inhibiting osteoclastogenesis and activating the Nrf2 pathway. This natural compound targets the Nrf2-mir-214-3p-Traf3 axis, offering a potential therapy for bone diseases.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Overactive osteoclastogenesis drives inflammatory bone loss, presenting a therapeutic target.
- Transcription factor enrichment analysis identified Nuclear factor erythroid 2-related factor 2 (Nrf2) as a key player in osteolysis.
Purpose of the Study:
- To investigate Forsythoside-β as a therapeutic agent for inflammatory bone loss.
- To elucidate the mechanism of action of Forsythoside-β involving Nrf2 signaling and microRNA regulation.
Main Methods:
- In-silico screening identified Forsythoside-β as a Nrf2-Keap1 protein-protein interaction inhibitor.
- In vivo and in vitro models of inflammatory osteoporosis were used to assess Forsythoside-β efficacy.
- Chromatin immunoprecipitation sequencing (ChIP-seq) analyzed Nrf2 binding to the mir-214-3p promoter.
Main Results:
- Forsythoside-β attenuated bone loss in vivo by inhibiting osteoclastogenesis and activating Nrf2 signaling.
- Forsythoside-β suppressed osteoclast differentiation, reactive oxygen species production, and induced Nrf2 nuclear translocation in vitro.
- Forsythoside-β decreased mir-214-3p expression, with Nrf2 identified as a regulator of this microRNA.
Conclusions:
- Forsythoside-β effectively prevents inflammatory bone loss by modulating the Nrf2-mir-214-3p-Traf3 axis.
- Forsythoside-β demonstrates potential as a therapeutic candidate for inflammatory bone loss disorders.
