Mounting evidence indicates that circular RNAs (circRNAs) have essential roles in several diseases, including periodontitis. Periodontal ligament stem cells (PDLSCs) exhibit potential for treating periodontitis accompanied by hypoxia. However, it is unclear how circRNA affects the osteogenesis of PDLSCs under hypoxia. In this study, a novel circRNA, hsa_circ_0003489, was found located at the gene for cyclin-dependent kinase 8 (CDK8) and referred to as circCDK8. The expression levels of circCDK8 and hypoxia-inducible factor-1α were significantly increased in periodontitis tissues, and the expression of circCDK8 was further confirmed in a hypoxia model using cobalt chloride (CoCl2 ). Interestingly, the results showed that the expression levels of osteoblast markers (RUNX2, ALP, OCN, and COL1A1) were increased in CoCl2 -treated PDLSCs at 6 and 12 h, but decreased at 24, 48, and 72 h. On the basis of bioinformatics and functional experiments, CoCl2 also induced endoplasmic reticulum stress, autophagy, and apoptosis of PDLSCs; the inhibition of autophagy promoted the osteogenic differentiation of CoCl2 -treated PDLSCs. Furthermore, circCDK8 overexpression induced autophagy and apoptosis through mTOR signaling, and circCDK8 silencing reversed the inhibitory effects of CoCl2 on osteogenic differentiation of PDLSCs. In conclusion, our results indicate that circCDK8 represses the osteogenic differentiation of PDLSCs by triggering autophagy activation in a hypoxic microenvironment. CircCDK8 could be a new therapeutic target of periodontitis.

中文翻译：

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CircCDK8通过在缺氧期间诱导内质网应激/自噬来调节PDLSCs的成骨分化和凋亡

越来越多的证据表明，环状 RNA（circRNA）在包括牙周炎在内的多种疾病中具有重要作用。牙周膜干细胞 (PDLSCs) 显示出治疗伴有缺氧的牙周炎的潜力。然而，目前尚不清楚circRNA如何影响缺氧条件下PDLSCs的成骨。在这项研究中，发现了一种新的 circRNA hsa_circ_0003489，它位于细胞周期蛋白依赖性激酶 8 (CDK8) 的基因上，称为 circCDK8。circCDK8和缺氧诱导因子-1α的表达水平在牙周炎组织中显着增加，在使用氯化钴（CoCl2）的缺氧模型中进一步证实了circCDK8的表达。有趣的是，结果显示成骨细胞标志物（RUNX2、ALP、OCN 和 COL1A1）的表达水平在 CoCl2 处理的 PDLSC 中在 6 和 12 小时增加，但在 24、48 和 72 小时下降。在生物信息学和功能实验的基础上，CoCl2还诱导了PDLSCs的内质网应激、自噬和凋亡；自噬的抑制促进了 CoCl2 处理的 PDLSCs 的成骨分化。此外，circCDK8过表达通过mTOR信号诱导自噬和细胞凋亡，circCDK8沉默逆转了CoCl2对PDLSCs成骨分化的抑制作用。总之，我们的结果表明，circCDK8 通过在缺氧微环境中触发自噬激活来抑制 PDLSCs 的成骨分化。CircCDK8 可能成为牙周炎的新治疗靶点。和 PDLSCs 的凋亡；自噬的抑制促进了 CoCl2 处理的 PDLSCs 的成骨分化。此外，circCDK8过表达通过mTOR信号诱导自噬和细胞凋亡，circCDK8沉默逆转了CoCl2对PDLSCs成骨分化的抑制作用。总之，我们的结果表明，circCDK8 通过在缺氧微环境中触发自噬激活来抑制 PDLSCs 的成骨分化。CircCDK8 可能成为牙周炎的新治疗靶点。和 PDLSCs 的凋亡；自噬的抑制促进了 CoCl2 处理的 PDLSCs 的成骨分化。此外，circCDK8过表达通过mTOR信号诱导自噬和细胞凋亡，circCDK8沉默逆转了CoCl2对PDLSCs成骨分化的抑制作用。总之，我们的结果表明，circCDK8 通过在缺氧微环境中触发自噬激活来抑制 PDLSCs 的成骨分化。CircCDK8 可能成为牙周炎的新治疗靶点。总之，我们的结果表明，circCDK8 通过在缺氧微环境中触发自噬激活来抑制 PDLSCs 的成骨分化。CircCDK8 可能成为牙周炎的新治疗靶点。总之，我们的结果表明，circCDK8 通过在缺氧微环境中触发自噬激活来抑制 PDLSCs 的成骨分化。CircCDK8 可能成为牙周炎的新治疗靶点。