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MYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling

Author

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  • He Cao

    (The Third Affiliated Hospital of Southern Medical University
    Southern Medical University)

  • Panpan Yang

    (The Third Affiliated Hospital of Southern Medical University
    Southern Medical University)

  • Jia Liu

    (Affiliated Hospital of Youjiang Medical University for Nationalities)

  • Yan Shao

    (The Third Affiliated Hospital of Southern Medical University
    Southern Medical University)

  • Honghao Li

    (The Third Affiliated Hospital of Southern Medical University
    Southern Medical University)

  • Pinglin Lai

    (The Third Affiliated Hospital of Southern Medical University
    Southern Medical University)

  • Hong Wang

    (The Third Affiliated Hospital of Southern Medical University
    Southern Medical University)

  • Anling Liu

    (Southern Medical University)

  • Bin Guo

    (Southern Medical University)

  • Yujin Tang

    (Affiliated Hospital of Youjiang Medical University for Nationalities)

  • Xiaochun Bai

    (The Third Affiliated Hospital of Southern Medical University
    Southern Medical University)

  • Kai Li

    (The Third Affiliated Hospital of Southern Medical University
    Southern Medical University
    The Third Affiliated Hospital of Southern Medical University)

Abstract

As the unique cell type in articular cartilage, chondrocyte senescence is a crucial cellular event contributing to osteoarthritis development. Here we show that clathrin-mediated endocytosis and activation of Notch signaling promotes chondrocyte senescence and osteoarthritis development, which is negatively regulated by myosin light chain 3. Myosin light chain 3 (MYL3) protein levels decline sharply in senescent chondrocytes of cartilages from model mice and osteoarthritis (OA) patients. Conditional deletion of Myl3 in chondrocytes significantly promoted, whereas intra-articular injection of adeno-associated virus overexpressing MYL3 delayed, OA progression in male mice. MYL3 deficiency led to enhanced clathrin-mediated endocytosis by promoting the interaction between myosin VI and clathrin, further inducing the internalization of Notch and resulting in activation of Notch signaling in chondrocytes. Pharmacologic blockade of clathrin-mediated endocytosis-Notch signaling prevented MYL3 loss-induced chondrocyte senescence and alleviated OA progression in male mice. Our results establish a previously unknown mechanism essential for cellular senescence and provide a potential therapeutic direction for OA.

Suggested Citation

  • He Cao & Panpan Yang & Jia Liu & Yan Shao & Honghao Li & Pinglin Lai & Hong Wang & Anling Liu & Bin Guo & Yujin Tang & Xiaochun Bai & Kai Li, 2023. "MYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41858-7
    DOI: 10.1038/s41467-023-41858-7
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    2. Jan M. van Deursen, 2014. "The role of senescent cells in ageing," Nature, Nature, vol. 509(7501), pages 439-446, May.
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