Background 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 (1). In addition, in vivo evidence confirmed the involvement of dopamine receptors (DR) in arthritis (2), and a subtype of DR was described to be expressed by in vitro differentiated human osteoclasts (3). 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 is 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.
Objectives The aim of this study is 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=6) 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. Expression of tyrosine hydroxylase (TH), the rate limiting enzyme for dopamine production, was quantified in untreated isolated osteoblasts 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 D1-like DR induced a significant dose-dependent increase of IL-6 release in RA compared to the untreated control (+79 ±43%, P<0.005). In contrast, no significant effects were detectable for OA osteoblasts. IL-8 release was not significantly altered in both RA and OA osteoblasts. TH was expressed in osteoblasts from 5 of 6 OA and from 2 of 4 RA patients, with expression levels even higher than in synovial fibroblasts (up to +50% in RA osteoblasts).
Conclusions 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. Expression of TH in osteoblasts suggests autocrine/paracrine effects of dopamine locally synthesized in the bone. These data underline the key involvement of the dopamine pathway in bone remodeling and joint erosion in RA.
Arthritis Rheumatol. 2014;66:2685–93
Mod. Rheumatol. 2011;21:260–6
Disclosure of Interest None declared