Exosomal miR-140-5p inhibits osteogenesis by targeting IGF1R and regulating the mTOR pathway in ossification of the posterior longitudinal ligament.
Exosomal miR-140-5p inhibits osteogenesis by targeting IGF1R and regulating the mTOR pathway in ossification of the posterior longitudinal ligament.
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外泌体 miR-140-5p 通过靶向 IGF1R 并调节后纵韧带骨化中的 mTOR 通路来抑制成骨
DOI：
10.1186/s12951-022-01655-8
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发表时间：
2022-10-15
影响因子：
10.2
通讯作者：
Chen, Xiongsheng
中科院分区：
文献类型：
--
作者：
Tang, Yifan;Sun, Yanqing;Zeng, Junkai;Yuan, Bo;Zhao, Yin;Geng, Xiangwu;Jia, Lianshun;Zhou, Shengyuan;Chen, Xiongsheng
后纵韧带骨化是一种致残性疾病，其发病机制尚不清楚，目前尚无有效的治疗和预防方法。外泌体miRNA在异位骨的成骨过程中起重要作用。因此，我们专注于OPLL细胞源性外泌体中miR-140- 5 p的下调，以探索外泌体miR-140- 5 p抑制OPLL成骨的机制。通过差速离心分离外泌体，并通过透射电子显微镜、纳米颗粒跟踪分析和外泌体标记物鉴定。提取exosomeRNA进行miRNA测序，发现差异表达的miRNAs，其中miR-140- 5 p表达显著下调。共聚焦显微镜用于追踪从OPLL细胞递送至人间充质干细胞（hMSC）的外泌体miR-140- 5 p。在体外实验中，我们证实了exosomal miR-140- 5 p通过靶向IGF 1 R和抑制IRS 1/PI 3 K/Akt/mTOR通路的磷酸化来抑制hMSCs的成骨分化。在体内，我们通过micro-CT和免疫组织化学评估证实了外泌体miR-140- 5 p抑制小鼠异位骨形成。我们发现exosomal miR-140- 5 p可以通过靶向IGF 1 R和调节mTOR通路来抑制hMSCs的成骨分化，这为OPLL的药物治疗和分子治疗提供了新的可能靶点。在线版本包含补充材料，可通过10.1186/s12951-022-01655-8获得。
Ossification of the posterior longitudinal ligament (OPLL) is a disabling disease whose pathogenesis is still unclear, and there are no effective cures or prevention methods. Exosomal miRNA plays an important role in the osteogenesis of ectopic bone. Therefore, we focused on the downregulation of miR-140-5p in OPLL cell-derived exosomes to explore the mechanism by which exosomal miR-140-5p inhibits osteogenesis in OPLL. Exosomes were isolated by differential centrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and exosomal markers. Exosomal RNA was extracted to perform miRNA sequencing and disclose the differentially expressed miRNAs, among which miR-140-5p was significantly downregulated. Confocal microscopy was used to trace the exosomal miR-140-5p delivered from OPLL cells to human mesenchymal stem cells (hMSCs). In vitro, we verified that exosomal miR-140-5p inhibited the osteoblast differentiation of hMSCs by targeting IGF1R and suppressing the phosphorylation of the IRS1/PI3K/Akt/mTOR pathway. In vivo, we verified that exosomal miR-140-5p inhibited ectopic bone formation in mice as assessed by micro-CT and immunohistochemistry. We found that exosomal miR-140-5p could inhibit the osteogenic differentiation of hMSCs by targeting IGF1R and regulating the mTOR pathway, prompting a further potential means of drug treatment and a possible target for molecular therapy of OPLL. The online version contains supplementary material available at 10.1186/s12951-022-01655-8.
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影响因子：
16.6
作者：
Li D;Liu J;Guo B;Liang C;Dang L;Lu C;He X;Cheung HY;Xu L;Lu C;He B;Liu B;Shaikh AB;Li F;Wang L;Yang Z;Au DW;Peng S;Zhang Z;Zhang BT;Pan X;Qian A;Shang P;Xiao L;Jiang B;Wong CK;Xu J;Bian Z;Liang Z;Guo DA;Zhu H;Tan W;Lu A;Zhang G
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1.2
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Lin X