Molecular Therapy: Nucleic Acids (Mar 2021)

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

  • Mengmeng Liang,
  • Xiaofan Yin,
  • Shuai Zhang,
  • Hongbo Ai,
  • Fei Luo,
  • Jianzhong Xu,
  • Ce Dou,
  • Shiwu Dong,
  • Qinyu Ma

DOI
https://doi.org/10.1016/j.omtn.2021.01.031
Journal volume & issue
Vol. 23
pp. 1191 – 1203

Abstract

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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.

Keywords