2. Academic Validation
  3. YY1/miR-140-5p/Jagged1/Notch axis mediates cartilage progenitor/stem cells fate reprogramming in knee osteoarthritis

YY1/miR-140-5p/Jagged1/Notch axis mediates cartilage progenitor/stem cells fate reprogramming in knee osteoarthritis

  • Int Immunopharmacol. 2023 Jun 7;121:110438. doi: 10.1016/j.intimp.2023.110438.
Yang Chen 1,  Guangneng Liao 2,  Ting Ma 3,  Lan Li 1,  Jing Yang 1,  Bin Shen 1,  Yanrong Lu 4,  Haibo Si 5
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery & Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Experimental Animal Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Department of Operating Room of Anesthesia Surgery Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 4 Department of Orthopedic Surgery & Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 5 Department of Orthopedic Surgery & Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
PMID: 37295026 DOI: 10.1016/j.intimp.2023.110438
Abstract

Osteoarthritis is a multifactorial disease characterized by cartilage degeneration, while cartilage progenitor/stem cells (CPCs) are responsible for endogenous cartilage repair. However, the relevant regulatory mechanisms of CPCs fate reprogramming in OA are rarely reported. Recently, we observed fate disorders in OA CPCs and found that microRNA-140-5p (miR-140-5p) protects CPCs from fate changes in OA. This study further mechanistically investigated the upstream regulator and downstream effectors of miR-140-5p in OA CPCs fate reprogramming. As a result, luciferase reporter assay and validation assays revealed that miR-140-5p targets Jagged1 and inhibits Notch signaling in human CPCs, and the loss-/gain-of-function experiments and rescue assays discovered that miR-140-5p improves OA CPCs fate, but this effect can be counteracted by Jagged1. Moreover, increased transcription factor Ying Yang 1 (YY1) was associated with OA progression, and YY1 could disturb CPCs fate via transcriptionally repressing miR-140-5p and enhancing the Jagged1/Notch signaling. Finally, the relevant changes and mechanisms of YY1, miR-140-5p, and Jagged1/Notch signaling in OA CPCs fate reprogramming were validated in rats. Conclusively, this study identified a novel YY1/miR-140-5p/Jagged1/Notch signaling axis that mediates OA CPCs fate reprogramming, wherein YY1 and Jagged1/Notch signaling exhibits an OA-stimulative role, and miR-140-5p plays an OA-protective effect, providing attractive targets for OA therapeutics.

Keywords

Cartilage progenitor/stem cells; Fate reprogramming; Jagged1; Osteoarthritis; Ying Yang 1; microRNA-140-5p.

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