Background/Purpose: A body of studies demonstrates the influence of the nervous system on the immune response. We recently described that dopamine, a neurotransmitter of the sympathetic nervous system, is locally produced by synovial fibroblasts of rheumatoid arthritis (RA) patients and influences in vitro cytokine release and inflammation. In addition, in vivo evidence confirmed the involvement of dopamine receptors (DR) in arthritis, and a subtype of DR was described to be expressed by in vitro differentiated human osteoclasts. These studies, together with the clinical evidence of an increased risk of osteoporosis in patients affected by Parkinson’s disease, suggest an involvement of dopamine in joint destruction during RA. The aim of this study was therefore not only to investigate the role of the dopamine pathway on bone remodeling in RA patients, but also to unravel new pathways involved in joint destruction.

Methods: Bone tissue was obtained from osteoarthritis (OA, n=5) and RA (n=4) patients during knee joint replacement surgery. Osteoblasts were isolated from the bone spongiosa. Immunohistochemistry of paraffin-embedded bone samples and immunocytochemistry of isolated osteoblasts were performed using antibodies against the five subtypes of DR (D1 to D5). Isolated osteoblasts were treated with specific DR agonists for 24 h or 7 d. IL-6 and IL-8 were quantified after 24 h stimulation by ELISA, and expression of osteoblast activation markers was quantified after 7 d stimulation by real-time PCR. Mann Whitney test was used for statistical data analysis.

Results: Dopamine receptors D1, D3 and D4 could be detected by immunohistochemistry in the bone remodeling zone of RA patients while OA samples did not express these receptors in the bone remodeling zone. Dopamine receptor subtypes D1, D2, D3 and D5 were present on isolated osteoblasts, with stronger expression in RA compared to OA. Stimulation of DR with specific agonists induced a significant dose-dependent increase of IL-6 release in RA compared to the untreated control (D1-like agonist: +79 ±43%, P<0.005. D2-like agonist: +70 ±49%. n=4), but no significant effects were detectable for OA osteoblasts. IL-8 release was not significantly altered in both, RA and OA osteoblasts. DR activation inhibited mRNA expression of osteocalcin, collagen type I, alkaline phosphatase and osteoprotegerin in RA osteoblasts (up to -10% compared to untreated control, n=2). 

Conclusion: Dopamine receptors are upregulated in the bone remodeling zone of RA patients and their activation seems to have proinflammatory effects and to inhibit osteoblast activation. These data suggest an involvement of the dopamine pathway in bone remodeling and joint erosion in RA, and could open future perspectives to target joint destruction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dopamine-pathway-and-bone-metabolism-in-arthritis/