Article
Strong and age-dependent effects of dopamine on fibroblast aggressive phenotype in rheumatoid arthritis and osteoarthritis patients
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Authors
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Lina van Nie
- Justus-Liebig-Universität Gießen, Kerckhoff-Klinik GmbH, Rheumatologie u. klinische Immunologie, Osteologie, Physikalische Therapie, Bad Nauheim
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Stefan Rehart
- Agaplesion Markus Krankenhaus, Akademisches Lehrkrankenhaus der Johann Wolfgang Goethe-Universität, Klinik für Orthopädie und Unfallchirurgie, Frankfurt/Main
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Elena Neumann
- Justus-Liebig-Universität Gießen, Kerckhoff-Klinik GmbH, Rheumatologie u. klinische Immunologie, Osteologie, Physikalische Therapie, Bad Nauheim
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Ulf Müller-Ladner
- Justus-Liebig-Universität Gießen, Kerckhoff-Klinik GmbH, Rheumatologie u. klinische Immunologie, Osteologie, Physikalische Therapie, Bad Nauheim
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Silvia Capellino
- IfADo - Leibniz Research Centre for Working Environment and Human Factors, Neuroimmunology, Dortmund
| Published: | September 4, 2017 |
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Outline
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Background: Preventing synovial fibroblasts (SF) from migrating into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA) in order to avoid joint destruction and disability. Recently, we described the production of dopamine by synovial cells in rheumatoid arthritis patients. Receptors for dopamine (DRs) were also strongly expressed in inflamed RASF, supporting the idea that locally produced dopamine acts in a paracrine/autocrine manner. Based on these results, we hypothesize that dopamine-dependent pathways play a role in local joint invasion and destruction by fibroblasts in RA patients.
Aim of this study is therefore to further investigate a possible dopamine-mediated impact on joint invasion and destruction in RA
Methods: SF were obtained from RA and osteoarthritis (OA) patients undergoing knee joint replacement surgery (mean age: 74.3 ±11.3yrs at OA and 73.7 ± 10.3 yrs at RA patients). To investigate dopamine receptor (DR) distribution within the RA synovium and in the invasion zone, immunohistochemistry was performed for all five DR-subtypes. Migration- and motility-assays and ELISAs for MMP3 and proMMP1 levels were performed under D1-like (D1DR and D5DR) and D2-like (D2DR, D3DR and D4DR) DR stimulation.
Results: D1DR, D4DR and D5DR are higher expressed nearby the invasion zone compared to the sublining layers. Overall DR expression was higher in RA synovium compared to OA.
Migration of RASF and OASF is highly correlated with the patients’ age at surgery. While younger patients (≤ 75years) show an increase in migration up to +78%, older patients (>75years) show a reduced migration up to -50% compared to untreated control (OA n=8; RA n=7). We observed no difference between RA and OA patients and between D1-like and D2-like receptor stimulation. The same effect was described in the motility assay (OA n=5; RA n=6). MMP3 and proMMP1 levels are altered under DR activation (OA n=3; RA n=3).
Conclusion: Taken together, our results suggest a direct role of dopamine on the fibroblast aggressive phenotype in arthritis. Therefore, synovial dopamine pathway is a potential therapeutic target of RA. Age-dependent effects on DR expression and dopamine binding affinity to the DR are under investigation.
