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A novel mechanism for inhibiting proliferation of rheumatoid arthritis fibroblast-like synoviocytes: geniposide suppresses HIF-1α accumulation in the hypoxic microenvironment of synovium

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Abstract

Objective

The excessive proliferation of fibroblast-like synoviocytes (FLSs) is a key inducement for the occurrence and development of rheumatoid arthritis (RA). Hypoxia inducible factor-α (HIF-α) accumulation is involved in the regulation of cell biological functions in the hypoxic microenvironment of synovium. This study aimed to investigate the roles of HIF-α and its level regulator prolyl hydroxylases (PHDs) in FLSs proliferation and to explore the regulatory effect of geniposide (GE).

Materials and methods

Adjuvant arthritis rats and RA-FLSs cell line MH7A were taken as the research objects. MH7A cells were incubated in a hypoxic chamber with 2% O2 for hypoxia treatment. CCK-8, FACS, EdU and Western blot assays were performed to evaluate MH7A cells proliferation. Iron assay was conducted to determine intracellular Fe2+ level.

Results

MH7A cells proliferation was significantly enhanced under hypoxia, accompanied by an increase of HIF-1α level. Decreased HIF-1α level by PX-478 inhibited MH7A cells proliferation. Furthermore, PHD2 was highly expressed in vivo and in vitro, and played a key role in modulation of HIF-1α protein level, which was confirmed by PHD2 inhibitor IOX4 and proteasome inhibitor MG132. GE treatment alleviated synovial hyperplasia in AA rats and inhibited MH7A cells proliferation with a reduction in HIF-1α level. Fe2+ acts as an enzymatic cofactor to control PHD2 activity. Iron assay showed that GE reversed the decline of Fe2+ level in MH7A cells under hypoxia.

Conclusion

GE attenuates abnormal proliferation of RA-FLSs via inhibiting HIF-1α accumulation through enhancement of PHD2 activity.

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Acknowledgements

All the animal experiments were approved by the experimental animal ethics committee of Anhui University of Chinese Medicine (No. AHUCM-rats-2021049).

Funding

This work was supported by the National Natural Science Foundation of China (No 81473400; No 81874360).

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Authors and Affiliations

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

    Peirong Gan, Minghui Sun, Hong Wu, Jiangtao Ke, Xintong Dong & Fangyuan Chen

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

    Peirong Gan, Minghui Sun, Hong Wu, Jiangtao Ke, Xintong Dong & Fangyuan Chen

  3. Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China

    Peirong Gan, Minghui Sun, Hong Wu, Jiangtao Ke, Xintong Dong & Fangyuan Chen

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  1. Peirong Gan
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  2. Minghui Sun
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  3. Hong Wu
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  4. Jiangtao Ke
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Contributions

All authors contributed to the study conception and design. Experiment implementation and data analysis were performed by PG, MS, Professor HW, JK, XD and FC. The manuscript was written by PG.

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Correspondence to Hong Wu.

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Gan, P., Sun, M., Wu, H. et al. A novel mechanism for inhibiting proliferation of rheumatoid arthritis fibroblast-like synoviocytes: geniposide suppresses HIF-1α accumulation in the hypoxic microenvironment of synovium. Inflamm. Res. 71, 1375–1388 (2022). https://doi.org/10.1007/s00011-022-01636-5

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  • DOI: https://doi.org/10.1007/s00011-022-01636-5

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