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Mesenchymal Stem Cell–Derived Extracellular Vesicles Inhibit Osteoporosis via MicroRNA-27a-Induced Inhibition of DKK2-Mediated Wnt/β-Catenin Pathway

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Abstract

Osteoporosis (OP) is a systemic skeletal disease that promotes bone fragility and the risk of fractures. Recent studies have shown the relevance of microRNAs (miRNAs) in the development of OP. This study aimed to evaluate the possible mechanisms of action underlying miR-27a loaded by mesenchymal stem cell (MSC)–derived extracellular vesicles (MSC-EVs) in OP. Serum samples from OP patients and normal controls were collected for miRNA microarray analysis. The expression of filtered miRNA was upregulated in osteoblasts (OB) and osteoclasts (OCs) for biological activity assessment. After developing OP mice using ovariectomy (OVX) and confirming OP, the miR-27a expression level was upregulated in mice by MSC-EV application. Dual-luciferase assays were conducted to validate the relationship between miR-27a and DKK2 expression. The poor expression of miR-27a was observed in patients with OP. miR-27a increased the expression of OB markers, the number of ALP-positive cells, and the number of calcium nodules in OCs. In OVX mice, miR-27a increased bone density, improved bone structure damage recovery, decreased the levels of bone resorption markers, and decreased OC number. miR-27a transmitted by MSC-EVs interacted with DKK2. MSC-EVs exerted the same protective effects as miR-27a on OP, whereas miR-27a inhibitor abolished the attenuating effects of MSC-EVs. In contrast, DKK2 depletion reversed the stimulatory effects of the miR-27a inhibitor on OP. The Wnt/β-catenin pathway was activated upon MSC-EV application and DKK2 silencing and was impaired upon the downregulation of the expression of miR-27a. MSC-EVs are effective in preventing mouse OP. This mechanism is mediated by the miR-27a/DKK2/Wnt/β-catenin signaling pathway.

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DATA AVAILABILITY

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Stomatology, Tibet Corps Hospital, Chinese People’s Armed Police Forces, Chengguan District, Tibet Autonomous Region, No. 77, Sala Road, Zhaxi Street, 850000, Lhasa, People’s Republic of China

    Yan Wang

  2. Orthopaedic Sports Medicine Center, Jilin City People’s Hospital, 132012, Jilin, People’s Republic of China

    Xiaoqi Zhou

  3. Department of Orthopedics, Affiliated Hospital of Beihua University, 132012, Jilin, People’s Republic of China

    Dalin Wang

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YW: conception and design of the research, analysis, and interpretation of data; XQZ: acquisition of data and statistical analysis; DLW: drafting the manuscript, revision of manuscript for important intellectual content; all authors read and approved the final manuscript.

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Correspondence to Yan Wang.

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All human material was acquired with signed agreements from patients or normal controls following the Ethical Committee guidelines of Tibet Corps Hospital, Chinese People’s Armed Police Forces. All animal care and experimental procedures were approved by the Animal Study Committee of Tibet Corps Hospital, Chinese People’s Armed Police Forces and were performed in accordance with the guide for the use of laboratory animals.

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Wang, Y., Zhou, X. & Wang, D. Mesenchymal Stem Cell–Derived Extracellular Vesicles Inhibit Osteoporosis via MicroRNA-27a-Induced Inhibition of DKK2-Mediated Wnt/β-Catenin Pathway. Inflammation 45, 780–799 (2022). https://doi.org/10.1007/s10753-021-01583-z

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