Circ_0011058 alleviates RA pathology through the circ_0011058/miR-335-5p/CUL4B signal axis

Abstract

Our previous study found that Cullin 4B (CUL4B) inhibited rheumatoid arthritis (RA) pathology through glycogen synthase kinase-3beta (GSK3β)/canonical Wnt signalling pathway. In this work, pre-experiment and bioinformatics analysis suggested that circ_0011058 may lead to the up-regulation of CUL4B expression by inhibiting miR-335-5p. Therefore, we studied whether circ_0011058 can promote the expression of CUL4B through sponging the miR-335-5p and further promote the pathological development of RA. Bioinformatics prediction, real-time quantitative PCR (RT-qPCR), western blot (WB), double luciferase reporter gene and other relevant methods were used to study the inhibition of circ_0011058 on RA pathology and its molecular mechanism. Results showed that the expression of circ_0011058 was significantly increased in adjuvant arthritis (AA) rats and RA fibroblast-like synoviocytes (FLS). The knockout of circ_0011058 inhibited the proliferation of AA FLS and RA FLS, decreased the levels of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), and inhibited the expression of matrix metalloproteinase 3 (MMP3), fibronectin, which showed that circ_0011058 had a strong role in promoting RA pathology. Furthermore, miR-335-5p expression was reduced in AA rats and RA FLS. The highly expressed circ_0011058 directly sponged the miR-335-5p, which led to the increase of CUL4B expression and promoted the activation of the GSK3β/canonical signalling pathway. Finally, we confirmed that miR-335-5p mediated the roles of circ_0011058 in promoting RA pathological development, which showed that the circ_0011058/miR-335-5p/CUL4B signal axis was involved in RA pathology. This work was of great significance for clarifying the roles of circ_0011058 in RA pathology, and further work was needed to establish whether circ_0011058 was a potential therapeutic target or diagnostic marker for RA.

Graphical Abstract

Keywords:

• Rheumatoid arthritis
• circ_0011058
• miR-335-5p
• CUL4B
• canonical wnt signalling pathway

Acknowledgements

We thank the National Natural Science Foundation of China, Anhui Provincial Department of Science and Technology, Anhui Provincial Department of Education and Anhui University of traditional Chinese medicine for their support to this work.

Disclosure statement

Ethics approval and consent to participate

The clinical sample study was approved by the Fourth Affiliated Hospital of Anhui Medical University. All participants signed the informed consent, and the ethics review approval document No.: PJ-YX2021-026. The animal experiment was approved by the animal ethics committee of Anhui University of Chinese medicine (AHUCM-rats-2022115).

Consent for publication

This manuscript was published with the approval of all authors, and there was no conflict of interest in the submission.

Availability of data and material

Study raw data were provided by the corresponding authors upon request.

Competing interests

We confirm that there are no conflicts of interest in this publication and no financial support that has an impact on this work.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (82274310), Anhui Science and Technology Department (2022e07020028), Anhui Education Department (KJ2021A0588, KJ2021A0606, gxgwfx2022019), Anhui University of Chinese medicine (2020rcZD001, 2022BHTNXA05), and Anhui Administration of Traditional Chinese Medicine (2022CCYB10).