PMID- 36344492 OWN - NLM STAT- MEDLINE DCOM- 20221114 LR - 20230121 IS - 2041-4889 (Electronic) VI - 13 IP - 11 DP - 2022 Nov 7 TI - CircFOXO3 protects against osteoarthritis by targeting its parental gene FOXO3 and activating PI3K/AKT-mediated autophagy. PG - 932 LID - 10.1038/s41419-022-05390-8 [doi] LID - 932 AB - Osteoarthritis (OA) is a degenerative joint disorder causing pain and functional disability. Emerging evidence reveals that circular RNAs (circRNAs) play essential roles in OA progression and development. This study aimed to investigate the role of a novel circRNA factor, circFOXO3, in the progression of OA and elucidate its underlying molecular mechanism. The function of circFOXO3 in OA and interaction between circFOXO3 and its downstream mRNA target, forkhead box O3 (FOXO3), were evaluated by western blot (WB), immunofluorescence (IF), RNA immunoprecipitation, reverse transcription-quantitative PCR (RT-qPCR), and fluorescence in situ hybridization (FISH). Upregulation of circFOXO3 and autophagic flux were detected both in vivo and in vitro by WB, transmission electron microscopy (TEM), IF, and immunohistochemistry (IHC). A mouse model of OA was also used to confirm the role of circFOXO3 in OA pathogenesis in vivo. Decreased expression of circFOXO3 in OA cartilage tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of the extracellular matrix (ECM). Mechanistically, circFOXO3 functioned in cartilage by targeting its parental gene FOXO3 and activating autophagy. Intra-articular injection of lentivirus-circFOXO3 alleviated OA in the mouse model. In conclusion, our results reveal the key role played by circFOXO3 in OA progression; circFOXO3 overexpression may alleviate apoptosis of chondrocytes and promote anabolism of the ECM via activation of FOXO3 and autophagy, providing a potentially effective novel therapeutic strategy for OA. CI - (c) 2022. The Author(s). FAU - Zhao, Chen AU - Zhao C AD - Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. FAU - Li, Xiaodong AU - Li X AD - Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. FAU - Sun, Guantong AU - Sun G AD - Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. FAU - Liu, Pengcheng AU - Liu P AD - Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. FAU - Kong, Keyu AU - Kong K AD - Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. FAU - Chen, Xuzhuo AU - Chen X AD - Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. FAU - Yang, Fei AU - Yang F AD - Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. feiyangyn@163.com. FAU - Wang, Xiaoqing AU - Wang X AUID- ORCID: 0000-0003-0051-1241 AD - Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. osteoclast2006@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221107 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - 0 (RNA, Circular) RN - 0 (FoxO3 protein, mouse) RN - 0 (Forkhead Box Protein O3) SB - IM MH - Animals MH - Mice MH - Apoptosis/genetics MH - Autophagy/genetics MH - Chondrocytes/metabolism MH - In Situ Hybridization, Fluorescence MH - *Osteoarthritis/pathology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - *RNA, Circular/genetics MH - *Forkhead Box Protein O3/genetics PMC - PMC9640610 COIS- The authors declare no competing interests. EDAT- 2022/11/08 06:00 MHDA- 2022/11/10 06:00 PMCR- 2022/11/07 CRDT- 2022/11/07 23:14 PHST- 2022/06/21 00:00 [received] PHST- 2022/10/28 00:00 [accepted] PHST- 2022/10/26 00:00 [revised] PHST- 2022/11/07 23:14 [entrez] PHST- 2022/11/08 06:00 [pubmed] PHST- 2022/11/10 06:00 [medline] PHST- 2022/11/07 00:00 [pmc-release] AID - 10.1038/s41419-022-05390-8 [pii] AID - 5390 [pii] AID - 10.1038/s41419-022-05390-8 [doi] PST - epublish SO - Cell Death Dis. 2022 Nov 7;13(11):932. doi: 10.1038/s41419-022-05390-8.