miR-1260b inhibits periodontal bone loss by targeting ATF6β mediated regulation of ER stress.
miR-1260b inhibits periodontal bone loss by targeting ATF6β mediated regulation of ER stress.
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miR-1260b通过靶向ATF6β介导的内质网应激调节抑制牙周骨丢失。
DOI：
10.3389/fcell.2022.1061216
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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作者：
外体microRNAs(MiRNAs)的表达受微环境的调控，适当的间充质干细胞(MSCs)刺激是提高MSCs旁分泌能力的策略之一。我们以前的工作表明，肿瘤坏死因子α诱导的人牙周炎间充质干细胞外切体可以作为牙周炎的治疗工具，而肿瘤坏死因子α诱导的外切体miR-1260b对于抑制牙槽骨丢失是必不可少的。然而，miR-1260b抑制破骨细胞生成的确切分子机制尚不完全清楚。在这里，我们发现激活转录因子-6β，一个新的以miR-1260b为靶向的基因，在内质网应激下对破骨细胞的发生起着关键的调控作用。实验小鼠牙周模型显示，内质网应激的诱导伴随着ATF6β表达的增强，局部应用mIR-1260b和ATF6siRNA的聚乙烯亚胺纳米粒(PEI-NPs)可显著抑制牙周骨吸收。在牙周膜细胞中，内质网应激诱导剂衣霉素增强了核因子受体激活剂κB配体的表达，而miR-1260b介导的下调β则抑制了核因子受体激活剂B配体的表达。此外，miR-1260b/ATF6β轴激活的PDL细胞的分泌体抑制了人外周血单核细胞的破骨细胞生成。提示MIR-1260b/ATF6β轴参与了内质网应激的调节，有望成为治疗牙周病的一种新的治疗策略。
The expression profiles of exosomal microRNAs (miRNAs) are regulated by the microenvironment, and appropriate priming with mesenchymal stem cells (MSCs) is one of the strategies to enhance the paracrine potency of MSCs. Our previous work demonstrated that exosomes from tumor necrosis factor (TNF)-α-primed human gingiva-derived MSCs (GMSCs) could be a therapeutic tool against periodontitis, and that TNFα-inducible exosomal miR-1260b is essential for the inhibition of alveolar bone loss. However, the precise molecular mechanism underlying miR-1260b-mediated inhibition of osteoclastogenesis is not yet fully understood. Here, we found that the activating transcription factor (ATF)-6β, a novel miR-1260b-targeting gene, is critical for the regulation of osteoclastogenesis under endoplasmic reticulum (ER) stress. An experimental periodontal mouse model demonstrated that induction of ER stress was accompanied by enhanced ATF6β expression, and local administration of miR-1260b and ATF6β siRNA using polyethylenimine nanoparticles (PEI-NPs) significantly suppressed the periodontal bone resorption. In periodontal ligament (PDL) cells, the ER stress inducer, tunicamycin, enhanced the expression of the receptor activator of NF-κB ligand (RANKL), while miR-1260b-mediated downregulation of ATF6β caused RANKL inhibition. Furthermore, the secretome from miR-1260b/ATF6β-axis-activated PDL cells inhibited osteoclastogenesis in human CD14+ peripheral blood-derived monocytes. These results indicate that the miR-1260b/ATF6β axis mediates the regulation of ER stress, which may be used as a novel therapeutic strategy to treat periodontal disease.