Dopamine induces in vitro migration of synovial fibroblast from patients with rheumatoid arthritis

Lina Van Nie,Ulf Müller-Ladner,Elena Neumann,Silvia Capellino,Marie-Lisa Hülser,Laura Salinas-Tejedor,Maurizio Cutolo,Stefan Rehart,Frank Fasbender,Nicole Dychus

doi:10.1038/s41598-020-68836-z

Abstract

Preventing synovial fibroblast (SF) migration into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA). As previous studies demonstrated that RASF and SF from osteoarthritis (OA) patients express dopamine receptors (DR), aim of the present study was to investigate the impact of dopamine on mobility of fibroblasts from patients with chronic arthritides. Synovial tissue and fibroblasts were obtained from RA and OA patients. Immunohistochemistry was performed for all DR-subtypes in the invasion zone. Migration- and motility-assays were performed under DR-stimulation. Cytokines were evaluated using ELISA. Expression of DRs was evaluated by flow cytometry, and DR activation was measured by xCELLigence real-time analysis.All DRs were expressed in RA invasion zone. Migration and motility of RASF and OASF were increased after DR stimulation in patients ≤ 75 years old. Synovial fibroblasts from older RA patients (> 75 years old) expressed lower levels of D1-, D2- and D4-DR than patients ≤ 75 years old. DR activation was not altered in older patients. Our results suggest a possible involvement of dopamine on migration of fibroblasts from arthritis patients. Therefore, the synovial dopaminergic pathway might represent a potential therapeutic target to interfere with progressive joint damage in RA patients.

Highlights

Preventing synovial fibroblast (SF) migration into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA)
The staining intensity of D1DR, D2DR and D5DR was stronger in the invasion zone than in the other layers of the synovial tissue in RA (Fig. 1c), and D3DR was significantly higher expressed in OA synovial tissue near the cartilage compared to the other layers of synovium (Fig. 1c)
Stimulation of D1-like dopamine receptors (DR) with Fenoldopam led to a strong increase of SF migration (Fig. 2a) in younger patients, whereas cell migration was gradually inhibited with increasing age (Fig. 2b)

Summary

Introduction

Preventing synovial fibroblast (SF) migration into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA). Abbreviations OA Osteoarthritis RA Rheumatoid arthritis SF Synovial fibroblasts DR Dopaminergic receptor RTCA Real time cell analysis FACS Fluorescent activated cell sorting (flow cytometry). The invasive phenotype of the activated fibroblasts is not dependent from inflammatory processes, as RASF are able to invade and destroy human cartilage and bone in the absence of immune c ells[2]. RA patients often develop restless leg syndrome, a disorder involving the dopaminergic s ystem[7] Despite these clinical evidences, a possible direct role for dopamine in arthritis was suggested only within the last years in RA patients[8] and in experimental a rthritis[9,10]

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