CircCDK8 regulates osteogenic differentiation and apoptosis of PDLSCs by inducing ER stress/autophagy during hypoxia

• Published in: Annals of the New York Academy of Sciences 2021-02, Vol.1485 (1), p.56-70
• Main Authors: Zheng, Jingjing, Zhu, Ximei, He, Yani, Hou, Siyu, Liu, Ting, Zhi, Keqian, Hou, Tiezhou, Gao, Ling
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase - genetics; Alkaline Phosphatase - metabolism; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Autophagy; Autophagy - drug effects; Autophagy - physiology; Bioinformatics; Biomedical materials; Cbfa-1 protein; Cell Proliferation - drug effects; Cell Proliferation - physiology; circCDK8; Cobalt; Cobalt - pharmacology; Cobalt chloride; Collagen (type I); Collagen Type I - genetics; Collagen Type I - metabolism; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Cyclin-Dependent Kinase 8 - genetics; Cyclin-Dependent Kinase 8 - metabolism; Differentiation (biology); Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kinases; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - physiology; Microenvironments; Osteocalcin - genetics; Osteocalcin - metabolism; Osteogenesis; Osteogenesis - drug effects; Osteogenesis - physiology; osteogenic differentiation; PDLSCs; Periodontal ligament; Periodontal Ligament - cytology; Periodontal Ligament - drug effects; Periodontitis; Periodontitis - genetics; Periodontitis - metabolism; Phagocytosis; RNA, Circular - genetics; RNA, Circular - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Stem cells; TOR protein
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/nyas.14483

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. In this study, we demonstrated that circCDK8 regulated autophagy in periodontal ligament stem cells. It was also confirmed that the hypoxic microenvironment activated autophagy in PDL tissues, inhibited osteogenic differentiation, and promoted apoptosis. CircCDK8 could be a new therapeutic target of periodontitis.