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Geniposide augments apoptosis in fibroblast-like synoviocytes by restoring hypoxia-enhanced JNK-BNIP3-mediated autophagy

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Abstract

Background

As the main effector cells of chronic inflammation and hyperplasia of synovium, fibroblast-like synoviocytes (FLSs) show abnormal proliferation and insufficient apoptosis in the hypoxic microenvironment, which is due to the increase of BNIP3-mediated autophagy. This study aimed to explore the mechanism of geniposide (GE) on hypoxia-induced hyper-proliferative FLSs with a focus on autophagy and the JNK-BNIP3 pathway.

Methods

The dynamic changes of autophagy, apoptosis, and hypoxia-related proteins in adjuvant arthritis (AA) rats were detected by immunohistochemistry and Western blot. The proliferation, autophagy, apoptosis, and mitochondrial state of FLSs were detected by CCK-8, flow cytometry, immunofluorescence, and transmission electron microscopy, respectively. Western blot, qRT-PCR, and co-immunoprecipitation were used to detect the expression of the JNK-BNIP3 pathway.

Results

The excessive accumulation of BNIP3 in the synovium of AA rats was accompanied by inhibition of apoptosis and an increase in autophagy. GE inhibited the expression of BNIP3, enhanced apoptosis, decreased autophagy, and improved chronic inflammation and hyperplasia of synovium. The amount of autophagy under different oxygen concentrations was the key to mediating the different survival rates of FLSs, and the inhibition of autophagy triggered apoptosis. GE suppressed the proliferation of FLSs and down-regulated autophagy, leading to the accumulation of ROS and the decrease of mitochondrial membrane potential, induced the increase of apoptosis, and suppressed the accumulation of BNIP3 and the hyperphosphorylation of JNK.

Conclusion

GE inhibited autophagy by restoring the hypoxia-induced activated JNK-BNIP3 pathway, inducing mitochondrial oxidative damage, augmented apoptosis, and decreased survival rate of FLSs.

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Data availability

All data generated during this study are included in this published article.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No 81874360, No 81473400, and No 81073122), the Major Natural Science Research Projects of Anhui Province Colleges and Universities (KJ2021ZD0060), and the Natural Science Research Project of Anhui Educational Committee (2022AH050453).

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Authors and Affiliations

  1. Key Laboratory of Xin’an Medicine, Ministry of Education, Hefei, 230012, China

    Deng Ran, Wang Yan, Bu Yanhong & Wu Hong

  2. School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China

    Deng Ran

  3. College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China

    Wang Yan, Bu Yanhong & Wu Hong

  4. Anhui Province Key Laboratory of Research &, Developmentof Chinese Medicine, Hefei, 230012, China

    Wang Yan, Bu Yanhong & Wu Hong

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Contributions

RD and HW contributed to the conception and design of the study. RD wrote the first draft of the manuscript. RD, YW, and YH B wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Wu Hong.

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Ran, D., Yan, W., Yanhong, B. et al. Geniposide augments apoptosis in fibroblast-like synoviocytes by restoring hypoxia-enhanced JNK-BNIP3-mediated autophagy. Inflamm. Res. 72, 1745–1760 (2023). https://doi.org/10.1007/s00011-023-01782-4

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