Abstract
Objective
To probe the performance of miR-337-3p on the facet joint osteoarthritis (FJOA) and its underlying mechanism.
Methods
qRT-PCR and Western blot were utilized to analyze the levels of miR-337-3p and DUSP1 in the synovial tissues from 36 FJOA patients and 10 healthy controls. The human synovial fibroblasts of FJOA were isolated and cultured followed by cell transfection. Then, cells were exposed to 10 ng/mL of IL-1β to induce inflammatory response of synovial fibroblasts. The alternation on cell biological function in cell models was determined. The binding of miR-337-3p and SKP2 was predicted by StarBase, TargetScan, DIANA-microT and miRmap, and further verified by RIP assay and dual-luciferase reporter assay. Co-IP experiment and ubiquitination assay were used to display the binding of SKP2 and DUSP1 as well as the ubiquitination and degradation of DUSP1. After that, the FJOA rat model was established and miR-337-3p mimic or negative control was given to rats by tail vein injection. The pathological changes of synovial tissues, synovitis score, and inflammation level in rats were assessed.
Results
The low expressions of miR-337-3p and DUSP1 were noticed in the synovial tissues of FJOA patients and in IL-1β-induced synovial fibroblasts, and highly expressed p-p38 MAPK was noticed. Upregulation of miR-337-3p/DUSP1 or downregulation of SKP2 inhibited IL-1β-induced proliferation and inflammatory response of synovial fibroblasts. SKP2 was the target gene of miR-337-3p, and SKP2 induced the ubiquitination and degradation of DUSP1. MiR-337-3p exerted a protective effect on FJOA rats by alleviating damage of rat synovial tissues, promoting cell apoptosis and repressing inflammatory response.
Conclusion
MiR-337-3p plays a protective role in FJOA by negatively targeting SKP2 to suppress DUSP1 ubiquitination and inactivate the p38 MAPK pathway.
Graphical abstract
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Data availability
The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- FJOA:
-
facet joint osteoarthritis
- OA:
-
osteoarthritis
- miRNAs:
-
microRNAs
- Co-IP:
-
co-immunoprecipitation
- Ni-NTA:
-
Ni-nitrilotriacetic acid
- H&E:
-
hematoxylin and eosin
- SD:
-
standard deviation
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Acknowledgements
Thanks to all the participants and contributors.
Funding
This research was funded by the grant from the Natural Science Foundation of Guangdong Province (Grant No. 2018A0303130183).
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X.Z. Zhou and S.S. Jian conceived the ideas. X.Z. Zhou and S.S. Jian designed the experiments. D.X. Luo, Y.Y. Wang, and W.Y. Xu performed the experiments. S.S. Jian and H. Zhang analyzed the data. L. Zhang and S.S. Jian provided critical materials. D.X. Luo and Y.Y. Wang wrote the manuscript. X.Z. Zhou supervised the study. All the authors have read and approved the final version for publication.
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The experimental etiquettes were carried out after approval and in accordance with the guidelines set by the Ethics Committee of the Guangdong Second Provincial General Hospital, and all the patients provided their written informed consent. The study was performed based on the Declaration of Helsinki. All of the experiments involving animals were in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health), and the experimental scheme was authorized by the Committee of Experimental Animals of Guangdong Second Provincial General Hospital. All surgery was performed aseptically and every attempt was made to minimize animal suffering.
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Jian, S., Luo, D., Wang, Y. et al. MiR-337-3p confers protective effect on facet joint osteoarthritis by targeting SKP2 to inhibit DUSP1 ubiquitination and inactivate MAPK pathway. Cell Biol Toxicol 39, 1099–1118 (2023). https://doi.org/10.1007/s10565-021-09665-2
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DOI: https://doi.org/10.1007/s10565-021-09665-2