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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Targeting FGFR3 is a Useful Therapeutic Strategy for Rheumatoid Arthritis Treatment

Author(s): Shan-Fu Yu, Tien-Tsai Cheng, Gong-Kai Huang, Chung-Yuan Hsu, Ying-Hsien Kao* and Yueh-Hua Chung

Volume 17, 2024

Published on: 13 October, 2023

Article ID: e18761429261684 Pages: 12

DOI: 10.2174/0118761429261684231002062505

open_access

Abstract

Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease in which TNF-α plays an important role. Fibroblast growth factor receptor 3 (FGFR3) is reportedly involved in RA by regulating the expression of inflammatory cytokines.

Objective: This study examined the expression profile of FGFR3 in human synovial biopsy tissues and evaluated its gene-silencing effects on behaviors of synovial cells.

Methods: Immunohistochemical staining was used to measure FGFR3 expression in human RA joint tissues. Cell proliferation, migration, and apoptosis assays were used to monitor behavioral changes in cultured synovial SW-982 cells with siRNA-mediated FGFR3 gene silencing. Immunofluorescent staining and western blotting were used to detect molecular changes in the FGFR3 gene-silenced cells.

Results: FGFR3 up-regulation was noted in both cytoplasms and nuclei of synovial cells in human RA joints. FGFR3 siRNA delivery experiments corroborated that FGFR3 knockdown decreased proliferation and migration, and triggered apoptosis of synovial cells. The FGFR3 gene knockdown enhanced constitutive expression of epithelial marker E-cadherin and conversely suppressed expression of epithelial-mesenchymal transition (EMT) markers, including Snail, fibronectin, and vimentin. In addition, FGFR3 silencing significantly reduced the constitutive expressions of TNF-α, transcription factor NF-κΒ, and downstream COX-2 protein and collagenolytic enzyme MMP-9. MAPK inhibition markedly suppressed constitutive levels of NF-κΒ, COX-2, and MMP-9.

Conclusion: Genetic interference of FGFR3 could modulate the expression of inflammatory mediators and EMT markers in the synovial cells. Targeting the FGFR3/MAPK signal axis may be considered a useful therapeutic strategy to ameliorate the development of RA.

Keywords: Epithelial-mesenchymal transition, FGFR3, Inflammation, Rheumatoid arthritis, Synoviocytes, TNF-α.

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