Li LP, Chen XY, Liu HB, Zhu Y, Xie MJ, Li YJ, Luo M, Albahde M, Zhang HY, Lou JY. Oxidative stress-induced circSOD2 inhibits osteogenesis through sponging miR-29b in metabolic-associated fatty liver disease. World J Gastroenterol 2025; 31(9): 98027 [DOI: 10.3748/wjg.v31.i9.98027]
Corresponding Author of This Article
Jian-Ying Lou, Professor, Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88# Jiefang Road, Shangcheng District, Hangzhou 310009, Zhejiang Province, China. loujianying@zju.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Liang-Ping Li, Yi Zhu, Min-Jie Xie, Yong-Jian Li, Meng Luo, Mugahed Albahde, Jian-Ying Lou, Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Xiao-Ying Chen, Department of Emergency Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Hong-Bo Liu, Hong-Yu Zhang, Department of General Surgery, The People’s Hospital of Songyang, Lishui 323400, Zhejiang Province, China
Co-first authors: Liang-Ping Li and Xiao-Ying Chen.
Author contributions: Lou JY and Liu HB designed the research study; Li LP, Chen XY and Xie MJ performed the research; Li YJ, Luo M and Zhang HY analyzed the results; Li LP, Zhu Y and Albahde M wrote the manuscript; Lou JY supervised and supported the study; All authors reviewed the manuscript.
Supported by the National and Zhejiang Provincial Administration of Traditional Chinese Medicine Co-construction Project, No. GZY-ZJ-KJ-24080; and the Medical Science and Technology Project of Zhejiang Province, No. 2024XY228.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine, No. IRB-2022-1333.
Institutional animal care and use committee statement: All animal experiments were approved by the Institutional Animal Care and Use Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine, No. AIRB-2022-1453. Healthy 8-week-old male C57BL/J6 mice were purchased from the Laboratory Animal Center of Zhejiang University.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data used to support the findings of this study are available from the corresponding author upon reasonable request at loujianying@zju.edu.cn.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jian-Ying Lou, Professor, Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88# Jiefang Road, Shangcheng District, Hangzhou 310009, Zhejiang Province, China. loujianying@zju.edu.cn
Received: June 16, 2024 Revised: November 24, 2024 Accepted: January 23, 2025 Published online: March 7, 2025 Processing time: 247 Days and 6.1 Hours
Abstract
BACKGROUND
Metabolic-associated fatty liver disease (MAFLD) is characterized by lipid accumulation in hepatocytes and is closely associated with oxidative stress. Increasing clinical evidence indicates that MAFLD is linked to bone metabolic disorders, including osteoporosis. Recent studies indicate that the expression profiles of liver circular RNAs (circRNAs) are altered in MAFLD. However, the effects of these changes on bone metabolism remain poorly understood.
AIM
To investigate the effects and mechanism of differently expressed circRNAs secreted by the liver on osteogenic differentiation in MAFLD.
METHODS
RNA sequencing was performed to identify highly expressed circRNAs in the liver, validated by quantitative real-time reverse transcription polymerase chain reaction, and localized using fluorescence in situ hybridization (FISH). A mouse model induced by a high-fat diet was used to simulate MAFLD.
RESULTS
CircSOD2 was significantly upregulated in liver tissues and primary hepatocytes from subjects with MAFLD. CircSOD2 was induced by oxidative stress and attenuated by antioxidants in the mouse model. In addition, circSOD2 was delivered from hepatocytes to bone marrow mesenchymal stem cells (BMSCs). Furthermore, circSOD2 inhibited the osteogenic differentiation of BMSCs and in vivo bone formation by sponging miR-29b. Moreover, miR-29b inhibition reversed the stimulatory effect of circSOD2 silencing on osteogenic differentiation of BMSCs and in vivo bone formation. Mechanistically, the interaction between circSOD2 and miR-29b confirmed through a luciferase reporter assay and the co-localization in the cytoplasm evidenced by FISH indicated that circSOD2 acted as a sponge for miR-29b.
CONCLUSION
This study provides a novel mechanism underlying the liver-bone crosstalk, demonstrating that circSOD2 upregulation in hepatocytes, induced by oxidative stress, inhibits osteogenic differentiation of BMSCs by sponging miR-29b. These findings offer a better understanding of the relationship between MAFLD and osteoporosis.
Core Tip: Emerging evidence indicates that metabolic-associated fatty liver disease (MAFLD) closely associated with oxidative stress, is linked to bone metabolic diseases. Altered expression profiles of liver circular RNAs (circRNAs) have been observed in MAFLD. This study explores the upstream and downstream mechanisms of circSOD2 upregulation in osteogenesis by identifying differentially expressed circRNAs in MAFLD livers. Results demonstrated that circSOD2 upregulation in hepatocytes induced by oxidative stress inhibits osteogenic differentiation of bone marrow mesenchymal stem cells by sponging miR-29b. These findings provide a better understanding of the relationship between MAFLD and osteoporosis from the perspective of circRNAs.
