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. 2025 Sep 26:1-18.
doi: 10.1080/03008207.2025.2565592. Online ahead of print.

Mechanical stimulation of extracellular vesicles secreted by bone marrow mesenchymal stem cells promotes osteoblast proliferation and differentiation by activating the Wnt/β - catenin signaling pathway

Hongwei Cui  1   2 , Yan Wang  2 , Dong Wang  2 , Hui Zhang  1   2 , Liyuan Zhou  1   2 , Mengran Qin  2 , Guang Li  2 , Tiancheng Ma  2 , Yanxin Li  2 , Benchao Dong  2 , Peichuan Yang  2 , Zhibin Zhang  2 , Jianxiong Ma  2 , Xinlong Ma  2
Affiliations

Mechanical stimulation of extracellular vesicles secreted by bone marrow mesenchymal stem cells promotes osteoblast proliferation and differentiation by activating the Wnt/β - catenin signaling pathway

Hongwei Cui et al. Connect Tissue Res. .

Abstract

Introduction: Osteoporosis is characterized by decreased bone mass, microstructural deterioration of bone tissue, and increased bone fragility. Bone marrow mesenchymal stem cells (BMSCs) are essential for bone growth and repair. Exosomes, which are key mediators of intercellular communication, participate in various biological processes. Although previous studies mainly focused on exosomes from non-stimulated cells during bone remodeling, this study aims to evaluate the therapeutic effects and mechanisms of exosomes derived from mechanically stimulated BMSCs (MS-Exo) compared to conventional exosomes in glucocorticoid-induced osteoporosis (GIOP).

Methods: An in vitro GIOP model was created by treating MC3T3-E1 osteoblasts with dexamethasone. A 10% strain was identified as the optimal mechanical stimulation intensity for generating MS-Exo. Cell proliferation was evaluated using CCK-8 and EdU assays, while osteogenic differentiation and mineralization were assessed with ALP and ARS staining. The expression of osteogenic marker genes was measured via qRT-PCR. The mechanisms of MS-Exo were further examined through transcriptomic analysis, immunofluorescence, and qRT-PCR, focusing on the Wnt/β-catenin signaling pathway and its downstream transcription factor TCF7.

Results: The findings showed that MS-Exo more effectively reversed dexamethasone-induced suppression of MC3T3-E1 cell proliferation, osteogenic differentiation, and mineralization compared to conventional exosomes. Transcriptomic analysis revealed significant enrichment of the Wnt/β-catenin signaling pathway. Experimental validation confirmed that MS-Exo activated this pathway, increasing the expression of β-catenin, LRP6, and TCF7, while decreasing GSK-3β. The pro-osteogenic effects of MS-Exo were partially reduced by the Wnt pathway inhibitor Dkk-1.

Conclusion: Exosomes derived from mechanically stimulated BMSCs promote osteoblast proliferation and differentiation by activating the Wnt/β-catenin signaling pathway and its transcription factor TCF7, providing a promising therapeutic strategy for GIOP.

Keywords: Bone marrow mesenchymal stem cell; TCF7; Wnt/β-catenin signaling; exosome; mechanical stimulation.

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