Huang Yiping, Liu Hao, Guo Runzhi, Han Yineng, Yang Yuhui, Zhao Yi, Zheng Yunfei, Jia Lingfei, Li Weiran
Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.
Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.
Front Cell Dev Biol. 2021 Feb 2;9:631181. doi: 10.3389/fcell.2021.631181. eCollection 2021.
Orthodontic tooth movement is achieved by periodontal tissue remodeling triggered by mechanical force. It is essential to investigate the reaction of periodontal ligament stem cells (PDLSCs) for improving orthodontic therapeutic approaches. Autophagy is an endogenous defense mechanism to prevent mechanical damage of environmental change. Long non-coding RNAs (lncRNAs) are key regulators in gene regulation, but their roles are still largely uncharacterized in the reaction of PDLSCs during orthodontic tooth movement. In this study, we showed that autophagy was significantly induced in PDLSCs under compressive force, as revealed by the markers of autophagy, microtubule-associated protein light chain 3 (LC3) II/I and Beclin1, and the formation of autophagosomes. After the application of compressive force, lncRNA FER1L4 was strongly upregulated. Overexpression of FER1L4 increased the formation of autophagosome and autolysosomes in PDLSCs, while knockdown of FER1L4 reversed the autophagic activity induced by mechanical force. In mechanism, FER1L4 inhibited the phosphorylation of protein kinase B (AKT) and subsequently increased the nuclear translocation of forkhead box O3 (FOXO3) and thus mediated autophagic cascades under compressive strain. In mouse model, the expression of Lc3 as well as Fer1l4 was increased in the pressure side of periodontal ligament during tooth movement. These findings suggest a novel mechanism of autophagy regulation by lncRNA during periodontal tissue remodeling of orthodontic treatment.
正畸牙齿移动是通过机械力触发牙周组织重塑来实现的。研究牙周膜干细胞（PDLSCs）的反应对于改进正畸治疗方法至关重要。自噬是一种内源性防御机制，可防止环境变化造成的机械损伤。长链非编码RNA（lncRNAs）是基因调控中的关键调节因子，但其在正畸牙齿移动过程中PDLSCs反应中的作用仍很大程度上未被阐明。在本研究中，我们发现，如自噬标志物微管相关蛋白轻链3（LC3）II/I和Beclin1以及自噬体的形成所示，在压缩力作用下PDLSCs中自噬被显著诱导。施加压缩力后，lncRNA FER1L4强烈上调。FER1L4的过表达增加了PDLSCs中自噬体和自溶酶体的形成，而敲低FER1L4则逆转了机械力诱导的自噬活性。机制上，FER1L4抑制蛋白激酶B（AKT）的磷酸化，随后增加叉头框O3（FOXO3）的核转位，从而在压缩应变下介导自噬级联反应。在小鼠模型中，牙齿移动期间牙周膜压力侧的Lc3以及Fer1l4表达增加。这些发现提示了正畸治疗牙周组织重塑过程中lncRNA调节自噬的新机制。
