Osteoclast-derived small extracellular vesicles induce osteogenic differentiation via inhibiting ARHGAP1

Activated osteoclasts release large amounts of small extracellular vesicles (sEVs) during bone remodeling. However, little is known about whether osteoclast-derived sEVs affect surrounding cells. In this study, osteoclasts were generated by stimulating bone marrow macrophages (BMMs) with macrophage...

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Veröffentlicht in:Molecular therapy. Nucleic acids 2021-03, Vol.23, p.1191-1203
Hauptverfasser: Liang, Mengmeng, Yin, Xiaofan, Zhang, Shuai, Ai, Hongbo, Luo, Fei, Xu, Jianzhong, Dou, Ce, Dong, Shiwu, Ma, Qinyu
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Sprache:eng
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Zusammenfassung:Activated osteoclasts release large amounts of small extracellular vesicles (sEVs) during bone remodeling. However, little is known about whether osteoclast-derived sEVs affect surrounding cells. In this study, osteoclasts were generated by stimulating bone marrow macrophages (BMMs) with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear actor κB ligand (RANKL). We performed microarray analysis of sEV-microRNAs (miRNAs)s secreted from osteoclast at different stages and identified four miRNAs that were highly expressed in mature osteoclast-derived sEVs. One of these miRNAs, miR-324, significantly induced osteogenic differentiation and mineralization of primary mesenchymal stem cells (MSCs) in vitro by targeting ARHGAP1, a negative regulator of osteogenic differentiation. We next fabricated an sEV-modified scaffold by coating decalcified bone matrix (DBM) with osteoclast-derived sEVs, and the pro-osteogenic regeneration activities of the sEV-modified scaffold were validated in a mouse calvarial defect model. Notably, miR-324-enriched sEV-modified scaffold showed the highest capacity on bone regeneration, whereas inhibition of miR-324 in sEVs abrogated these effects. Taken together, our findings suggest that miR-324-contained sEVs released from mature osteoclast play an essential role in the regulation of osteogenic differentiation and potentially bridge the coupling between osteoclasts and MSCs. [Display omitted] Liang et al. describe a novel mode of communication between osteoclasts and mesenchymal stem cells during bone remodeling. Specifically, miR-324-enriched sEVs derived from osteoclasts promote osteogenic differentiation via ARHGAP1/RhoA/ROCK signaling.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2021.01.031