Coumarin alleviates osteoarthritis by regulating senescence-associated secretory phenotype and inhibiting cell senescence: an experimental study

Liu Kaiwen, Ye Yuanlan, Guo Fengjin

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Journal of Chongqing Medical University ›› 2024, Vol. 49 ›› Issue (12) : 1556-1565. DOI: 10.13406/j.cnki.cyxb.003683
Basic research

Coumarin alleviates osteoarthritis by regulating senescence-associated secretory phenotype and inhibiting cell senescence: an experimental study

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Abstract

Objective To investigate the effect of coumarin on osteoarthritis（OA） and its specific mechanism of action. Methods Venny2.1.0 website was used to obtain the intersecting targets of coumarin and OA，STRING database was used to perform a protein-protein interaction（PPI） analysis，and Autodock vina1.1.2 was used to perform molecular docking between the targets of coumarin and the disease targets of OA. An in vitro experiment was conducted，and the cells were divided into control group，IL-1β group，and IL-1β+coumarin group. CCK-8 assay was used to observe the cytotoxicity of coumarin on C28/I2 cells，qPCR and immunofluorescence assay were used to measure the expression of OA-related markers and SASP factors in each group，and β-galactosidase staining was used to measure the level of cell senescence. Results A total of 196 action targets were obtained for coumarin，including 127 intersecting targets of coumarin and OA. PPI analysis obtained four possible core targets of coumarin in treating OA，i.e.，CCND1，EGFR，ERBB2，and MAPK14. Molecular docking showed that coumarin could form a relatively stable complex with the core targets CCND1，EGFR，ERBB2，and MAPK14. CCK-8 assay showed that treatment of C28/I2 cells with 5-15 μmol/L coumarin promoted cell proliferation，while treatment with coumarin at a concentration of >20 μmol/L inhibited viability（P<0.05）；in addition，10 μmol/L coumarin promoted cell proliferation at 24，48，and 72 hours（P<0.05），with the most significant proliferation at 48 hours（P<0.05）. The results of qPCR showed that treatment with 10 μmol/L coumarin for 48 hours could reduce the mRNA levels of the cell senescence marker genes p16 and p21 in C28/I2 cells，and β-galactosidase staining obtained consistent results with qPCR. There were significant reductions in the mRNA levels of the SASP factors IL-1β，IL-6，TNF-α，MMP9，and MMP13 after coumarin treatment（P<0.05）. Similarly，immunofluorescence assay also showed reductions in the expression levels of some SASP factors after coumarin treatment. Conclusion Coumarin may exert a therapeutic effect on OA by acting on the p38/MAPK14 pathway and inhibiting cell aging and cartilage decomposition caused by SASP.

Key words

cell senescence / senescence-associated secretory phenotype / osteoarthritis / coumarin / senescence-associated secretory phenotypic factors

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Liu Kaiwen , Ye Yuanlan , Guo Fengjin. Coumarin alleviates osteoarthritis by regulating senescence-associated secretory phenotype and inhibiting cell senescence: an experimental study. Journal of Chongqing Medical University. 2024, 49(12): 1556-1565 https://doi.org/10.13406/j.cnki.cyxb.003683

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