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Quercetin attenuates the symptoms of osteoarthritis in vitro and in vivo by suppressing ferroptosis via activation of AMPK/Nrf2/Gpx4 signaling.

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  • Additional Information
    • Source:
      Publisher: D. A. Spandidos Country of Publication: Greece NLM ID: 101475259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1791-3004 (Electronic) Linking ISSN: 17912997 NLM ISO Abbreviation: Mol Med Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: Athens, Greece : D. A. Spandidos
    • Subject Terms:
      NF-E2-Related Factor 2*/metabolism ; Osteoarthritis*/metabolism ; Osteoarthritis*/drug therapy ; Osteoarthritis*/pathology ; Ferroptosis*/drug effects ; Quercetin*/pharmacology ; AMP-Activated Protein Kinases*/metabolism ; Chondrocytes*/metabolism ; Chondrocytes*/drug effects ; Phospholipid Hydroperoxide Glutathione Peroxidase*/metabolism ; Signal Transduction*/drug effects; Animals ; Mice ; Male ; Disease Models, Animal ; Interleukin-1beta/metabolism ; Apoptosis/drug effects ; Mice, Inbred C57BL
    • Abstract:
      Osteoarthritis (OA) is a common joint disorder involving the cartilage and other joint tissues. Quercetin (QCT) serves a protective role in the development of OA. However, to the best of our knowledge, the regulatory mechanisms of QCT in the progression of OA have not yet been fully elucidated. In order to mimic a model of OA in vitro , IL‑1β was used to stimulate chondrocytes. Furthermore, an in vivo animal model of OA was induced by anterior cruciate ligament transection (ACLT). 5‑Ethynyl‑2'‑deoxyuridine assays, TUNEL assays, ELISAs, western blotting and immunohistochemical assays were conducted to assess the chondroprotective properties of QCT in the development of OA. The results revealed that 100 µM QCT significantly promoted the proliferation, reduced the apoptosis and inflammation, and inhibited the extracellular matrix (ECM) degradation in IL‑1β‑stimulated chondrocytes. Additionally, QCT attenuated the IL‑1β‑induced ferroptosis of chondrocytes, as demonstrated by the reduced lipid reactive oxygen species and Fe 2+ levels. Conversely, the inhibitory effects of QCT on the apoptosis and inflammatory responses were reversed by the activation of ferroptosis by erastin in IL‑1β‑stimulated chondrocytes. Furthermore, QCT significantly elevated the level of phosphorylated (p‑)5' AMP‑activated protein kinase (AMPK) and the levels of two negative regulators of ferroptosis [nuclear factor erythroid 2‑related factor 2 (Nrf2) and glutathione peroxidase 4 (Gpx4)] in IL‑1β‑stimulated chondrocytes. The AMPK inhibitor compound C notably reversed the promoting effects of QCT on phosphorylated‑AMPK, Nrf2 and Gpx4 expression in IL‑1β‑stimulated chondrocytes. Additionally, QCT markedly ameliorated the destruction and degradation of articular cartilage, and elevated the p‑AMPK, Nrf2 and Gpx4 levels in the mouse model of ACLT‑induced OA. Overall, the present study demonstrated that QCT inhibited the development of OA by suppressing ferroptosis via the activation of the AMPK/Nrf2/Gpx4 signaling pathway. These findings provide novel insights into the regulatory mechanisms of QCT for the treatment of patients with OA.
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    • Contributed Indexing:
      Keywords: 5' AMP‑activated protein kinase; ferroptosis; nuclear factor erythroid 2‑related factor 2; osteoarthritis; quercetin
    • Accession Number:
      0 (NF-E2-Related Factor 2)
      9IKM0I5T1E (Quercetin)
      EC 2.7.11.31 (AMP-Activated Protein Kinases)
      EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
      0 (Interleukin-1beta)
      EC 1.11.1.9 (glutathione peroxidase 4, mouse)
      0 (Nfe2l2 protein, mouse)
    • Publication Date:
      Date Created: 20241224 Date Completed: 20241224 Latest Revision: 20250111
    • Publication Date:
      20250111
    • Accession Number:
      PMC11711930
    • Accession Number:
      10.3892/mmr.2024.13425
    • Accession Number:
      39717946