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

作者：Cao, He; Yang, Panpan; Liu, Jia; Shao, Yan; Li, Honghao; Lai, Pinglin; Wang, Hong; Liu, Anling; Guo, Bin; Tang, Yujin; Bai, Xiaochun^*; Li, Kai^*

来源：Nature Communications, 2023, 14(1): 6190.

DOI：10.1038/s41467-023-41858-7

• CELLULAR SENESCENCE
• OSTEOARTHRITIS
• CELLS
• MECHANISMS
• CLEARANCE

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. @@@ Age is the greatest risk factor for osteoarthritis (OA) and chondrocyte senescence is an important cellular event that contributes to OA development. This study shows that clathrin-mediated endocytosis and activation of Notch signaling promotes articular chondrocyte senescence and OA development, which is negatively regulated by myosin light chain 3 (MYL3).

• 单位
  南方医科大学