兰克尔
细胞生物学
未折叠蛋白反应
化学
旁分泌信号
癌症研究
牙周纤维
间充质干细胞
微泡
小RNA
免疫学
内质网
生物
激活剂(遗传学)
医学
受体
生物化学
牙科
基因
作者
Chikako Hayashi,Takao Fukuda,Kentaro Kawakami,Masaaki Toyoda,Yuki Nakao,Yukari Watanabe,Takanori Shinjo,Tomomi Sano,Misaki Iwashita,Karen Yotsumoto,Miyu Shida,Takaharu Taketomi,Terukazu Sanui,Takeshi Uchiumi,Takashi Kanematsu,Fusanori Nishimura
标识
DOI:10.3389/fcell.2022.1061216
摘要
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.
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