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Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis

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Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objective

Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis.

Methods

First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot.

Results

The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1β, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS.

Conclusion

These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA.

Key Points

• The administration of berberine (BBR) dramatically alleviated the severity of CIA model with a decreased clinic score and joint inflammation.

• BBR inhibited the pyroptosis of RA-FLS by downregulating of NLRP3 inflammasomes and activating the Hippo signaling pathway, contributing to the suppression of RA progress.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

FLS:

Fibroblast-like synoviocytes

RA:

Rheumatoid arthritis

BBR:

Berberine

CIA:

Collagen-induced arthritis

HTDS:

High-throughput drug screening

CII:

Chicken type II collagen

AI:

Arthritis index

H&E:

Hematoxylin and eosin

IHC:

Immunohistochemistry

MPO:

Myeloperoxidase

PVDF:

Polyvinylidene fluoride

ELISA:

Enzyme-linked immunosorbent assay

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Funding

This study was financially supported by the Gansu Administration of Traditional Chinese Medicine (GZKP-2021-30); Lanzhou Science and Technology Bureau, science and technology planning project of Lanzhou (2020-XG-59); the Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital (No. CY2021-QN-B10); National Natural Science Foundation of China (No. 8196060067); Science and Technology Project of Gansu Province, Natural Science Foundation(22JR5RA955); Education Technology Innovation Project of Gansu Province, Young Doctor Foundation(2022B-057).

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Authors and Affiliations

  1. The Department of Rheumatology, The Second Hospital of Lanzhou University, Lanzhou, 730000, China

    Li Zhang, Juan Zhang, Xiao-Yuan Wang, Yan Zhang, Rui-Xue Duo & Hai-Li Shen

  2. The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China

    Li Zhang, Min Tan, Jing Mao, Juan Zhang, Xiao-Yuan Wang, Yan Zhang, Rui-Xue Duo, Jia-Yao Hao & Hai-Li Shen

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  1. Li Zhang
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Contributions

Conception and design of the research: LZ, H-LS

Acquisition of data: LZ, MT, JM, X-YW, J-YH

Analysis and interpretation of the data: LZ, JZ, YZ, R-XD

Statistical analysis: JM, MT

Obtaining financing: LZ, H-LS

Writing of the manuscript: LZ

Critical revision of the manuscript for intellectual content: LZ, H-LS

All authors read and approved the final draft. All authors have contributed significantly to the manuscript.

Corresponding author

Correspondence to Hai-Li Shen.

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Ethics approval and consent to participation

The study was conducted in accordance with the Declaration of Helsinki (as was revised in 2013). The study was approved by Ethics Committee of the Lanzhou University Second Hospital. Written informed consent was obtained from all participants. The study protocol was approved by the Laboratory Animal Ethics Committee of Lanzhou University Second Hospital and carried out according to the US Department of Health’s Guidelines for the Use and Care of Laboratory Animals.

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Zhang, L., Tan, M., Mao, J. et al. Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis. Clin Rheumatol 43, 959–969 (2024). https://doi.org/10.1007/s10067-024-06871-1

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