MYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling
© 2023. Springer Nature Limited..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 04. Okt., Seite 6190 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cao, He [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 02.11.2023 Date Revised 19.11.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-41858-7 |
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| Förderinstitution / Projekttitel: |
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NLM362877270 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Myosin Light Chains |2 NLM | |
| 700 | 1 | |a Yang, Panpan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Shao, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Honghao |e verfasserin |4 aut | |
| 700 | 1 | |a Lai, Pinglin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Anling |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Yujin |e verfasserin |4 aut | |
| 700 | 1 | |a Bai, Xiaochun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Kai |e verfasserin |4 aut | |
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