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Dimethyl Fumarate Inhibits Fibroblast Like Synoviocytes-mediated Inflammation and Joint Destruction in Rheumatoid Arthritis

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Abstract

Rheumatoid arthritis (RA) as a chronic inflammatory disorder affects around 1% of the world population. Fibroblast-like synoviocyte (FLS), one of the main cells in RA pathogenesis is characterized by hyperproliferation and resistance to apoptosis resulting to synovial hyperplasia. Dimethyl fumarate (DMF) has been licensed for the treatment of multiple sclerosis (MS) and psoriasis; however, its role in RA is unknown. DMF has immunomodulatory properties and may be considered as therapeutic approach in RA treatment. In this study, we aimed to investigate the effect of DMF on controlling FLS-mediated synovial inflammation and joint destruction in RA. FLSs were isolated from synovial tissues of 8 patients with RA and treated with DMF. Apoptosis rate was analyzed by Annexin V-FITC. Cell proliferation was measured by carboxyfluorescein succinimidyl ester (CFSE) dye. The matrix metalloproteinase 3 (MMP3) and NF-кB pathway protein (p65) mRNA expression were evaluated by RT-PCR. Also, the IL-6 production and lactate release were measured in FLS supernatant. DMF treatment decreased the cell proliferation and increased apoptosis in a dose dependent manner. DMF-treated FLS showed a reduction in IL-6 and lactate release. Moreover, it was revealed that DMF inhibited the expression of p65 and MMP3. Our data demonstrate that DMF treatment suppresses the aggressive and inflammatory features of RA FLSs. Our Results suggest that DMF might be expected to be evaluated as a therapy for RA.

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DATA AVAILABILITY

Data are available from the corresponding author upon request.

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ACKNOWLEDGEMENTS

The authors acknowledge Dr. Salman Ghaffari and Dr. Abolfazl Bagheri Fard, and members of orthopedic surgery for providing synovial tissue. We also thank Dr. Aref Hosseinian Amiri for valuable discussion.

Funding

This study was financially supported by a grant (grant number: 3123) of the Research and Technology Council of Mazandaran University of Medical Sciences.

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Authors and Affiliations

  1. Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Parisa Zafari, Fatemeh Faramarzi, Misagh Rajabinejad & Alireza Rafiei

  2. Department of Immunology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Mahdi Taghadosi

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  1. Parisa Zafari
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  2. Mahdi Taghadosi
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Contributions

P.Z., and A.R., contributed to overall project design. P.Z., and F.F., performed the research. M.R. analyzed the data and prepared the figures. P.Z and M.T., wrote the manuscript.

Corresponding author

Correspondence to Alireza Rafiei.

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Human and Animal Ethics

All procedures were carried out in accordance with guidelines of Mazandaran University of Medical Sciences (IR.MAZUMS.REC.1398.1364).

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Informed consent was obtained from all individual participants included in the study.

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Zafari, P., Taghadosi, M., Faramarzi, F. et al. Dimethyl Fumarate Inhibits Fibroblast Like Synoviocytes-mediated Inflammation and Joint Destruction in Rheumatoid Arthritis. Inflammation 46, 612–622 (2023). https://doi.org/10.1007/s10753-022-01759-1

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