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Extracellular vesicles from bone marrow mesenchymal stem cells alleviate osteoporosis in mice through USP7-mediated YAP1 protein stability and the Wnt/β-catenin pathway.

Authors
  • Wang, Xuepeng1
  • Zou, Chunchun2
  • Hou, Changju1
  • Bian, Zhenyu1
  • Jiang, Wu1
  • Li, Maoqiang3
  • Zhu, Liulong4
  • 1 Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, PR China. , (China)
  • 2 Department of Obstetrics and Gynecology, Hangzhou Third People's Hospital, Hangzhou 310009, Zhejiang, PR China. , (China)
  • 3 Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, PR China. Electronic address: [email protected]. , (China)
  • 4 Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, PR China. Electronic address: [email protected]. , (China)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Nov 01, 2023
Volume
217
Pages
115829–115829
Identifiers
DOI: 10.1016/j.bcp.2023.115829
PMID: 37748664
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have emerged as promising tools for promoting bone regeneration. This study investigates the functions of EVs derived from bone marrow-derived MSCs (BMSCs) in osteoporosis (OP) and the molecular mechanism. EVs were isolated from primary BMSCs in mice. A mouse model with OP was induced by ovariectomy. Treatment with EVs restored bone mass and strength, attenuated trabecular bone loss and cartilage damage, and increased osteogenesis while suppressing osteoclastogenesis in ovariectomized mice. In vitro, the EVs treatment improved the osteogenic differentiation of MC-3T3 while inhibiting osteoclastic differentiation of RAW264.7 cells. Microarray analysis revealed a significant upregulation of ubiquitin specific peptidase 7 (USP7) expression in mouse bone tissues following EV treatment. USP7 was found to interact with Yes1 associated transcriptional regulator (YAP1) and stabilize YAP1 protein through deubiquitination modification. YAP1-related genes were enriched in the Wnt/β-catenin signaling, and overexpression of YAP1 promoted the nuclear translocation of β-catenin. Functional experiments underscored the critical role of maintaining USP7, YAP1, and β-catenin levels in the pro-osteogenic and anti-osteoclastogenic properties of the BMSC-EVs. In conclusion, this study demonstrates that USP7, delivered by BMSC-derived EVs, stabilizes YAP1 protein, thereby ameliorating bone formation in OP through the Wnt/β-catenin activation. Copyright © 2023 Elsevier Inc. All rights reserved.

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