Extracellular Vesicles Derived Ectonucleoside Triphosphate Diphosphohydrolase 3 Alleviates Mitochondrial Dysfunction of Osteoarthritis Chondrocytes via Ectonucleotide Pyrophosphatase/Phosphodiesterase 1-Induced Suppression of the AKT/Notch2 Pathway.

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  • Author(s): Tang X;Tang X; He J; He J; Hao Y; Hao Y
  • Source:
    Journal of biochemical and molecular toxicology [J Biochem Mol Toxicol] 2024 Dec; Vol. 38 (12), pp. e70064.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Wiley Country of Publication: United States NLM ID: 9717231 Publication Model: Print Cited Medium: Internet ISSN: 1099-0461 (Electronic) Linking ISSN: 10956670 NLM ISO Abbreviation: J Biochem Mol Toxicol Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York, NY : Wiley, c1998-
    • Subject Terms:
    • Abstract:
      Osteoarthritis (OA) is the most common joint disease that usually starts from joint cartilage injury. Notch2, a versatile signaling in human development and diseases, was recently uncovered to be an important regulator in chondrocyte damage. However, in OA chondrocytes, how Notch2 activation is dysregulated is largely unknown. Here, integrated bioinformatic analysis was performed on GEO datasets (GSE199193 and GSE224255) to search potential extracellular vesicles (EVs) derived regulators of Notch2 in OA chondrocytes. Ectonucleoside triphosphate diphosphohydrolase 3 (Entpd3), a most differentially expressed gene both in LPS-induced macrophage EV and Notch2 mutant chondrocytes, was screened as the candidate regulator of Notch2 in OA chondrocytes. Gain-of-function experiments in cultured human chondrocytes revealed that recombinant Entpd3 protein and macrophage EV both had a protective effect on LPS-induced inflammation, oxidative stress, apoptosis, and collagen loss in chondrocytes. In terms of mechanism, Entpd3 directly interacted with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and suppressed AKT/Notch2-mediated mitochondrial dysfunction. Finally, we verified that either macrophage EV administration or Entpd3 overexpression was able to alleviate osteoarthritis in mice in vivo. In conclusion, Entpd3 is identified as a new regulator in OA, which alleviates mitochondrial dysfunction induced chondrocyte damage via ENPP1-induced suppression of the AKT/Notch2 pathway.
      (© 2024 Wiley Periodicals LLC.)
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    • Contributed Indexing:
      Keywords: Entpd3/ENPP1; Notch2; extracellular vesicles; mitochondrial dysfunction; osteoarthritis chondrocytes
    • Accession Number:
      EC 3.1.4.- (Phosphoric Diester Hydrolases)
      0 (Receptor, Notch2)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
      EC 3.6.1.- (Pyrophosphatases)
      EC 3.1.4.1 (ectonucleotide pyrophosphatase phosphodiesterase 1)
      0 (NOTCH2 protein, human)
    • Publication Date:
      Date Created: 20241121 Date Completed: 20241121 Latest Revision: 20241121
    • Publication Date:
      20241121
    • Accession Number:
      10.1002/jbt.70064
    • Accession Number:
      39569601