Oxidative stress-induced circSOD2 inhibits osteogenesis through sponging miR-29b in metabolic-associated fatty liver disease

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.

Keywords: Circular RNAs; MicroRNAs; Oxidative stress; Osteogenesis; Non-alcoholic fatty liver disease; 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.