Activation of Melanocortin Receptor 3 as a new strategy to control experimental and rheumatoid arthritis

Study Objective The anti‐inflammatory properties of melanocortin peptides have long been established, though their main molecular target(s) is still elusive. Two receptors (MC1R and MC3R) have been suggested as their main target, but the patho‐physiological impact of this important homeostatic anti‐inflammatory system is unclear: we focused here on experimental and rheumatoid (RA) arthritis. Methods Mouse Studies (1) Arthritis was induced by K/BxN serum transfer (200 μl) into wild type (WT), recessive yellow e/e ( Mc1r inactive mutant) and Mc3r −/− mice and disease profiles monitored. (2) Gene expression analysis was performed in arthritic paw joints using qPCR. (3) Daily treatment with vehicle or D[Trp 8 ]‐γ‐MSH (MC3R agonist) was given to WT and Mc3r −/− mice (20 μg) induced with K/BxN arthritis and disease profiles assessed. Human Studies qPCR was used to analyse MCR and/or pro‐inflammatory cytokine mRNA levels in RA synovium transplanted into SCID mice treated with D[Trp 8 ]‐γ‐MSH. Results Upon K/BxN serum transfer, Mc3r −/− mice displayed a marked disease exacerbation whereas no different profile of disease development was displayed by the Mc1r mutant and WT mice. This heightened presence of disease in Mc3r −/− null mice was confirmed by histological analysis of paw joints. At peak of arthritic profile (D6), mRNA analysis revealed up‐regulation of Rankl, Mcp‐1, Nos2 and Il‐1 β , Il‐6 in Mc3r −/− mice compared to WT. Treatment of arthritic mice with D[Trp 8 ]‐γ‐MSH significantly attenuated disease. In another preclinical model, stimulation of human MC3R with D[Trp 8 ]‐γ‐MSH inhibited human IL‐1β, IL‐6, TNF‐α and RANKL gene expression in RA synovium transplanted into SCID mice. Conclusions These findings identify MC3R‐mediated signaling as a novel anti‐inflammatory pathway for innovative therapeutic targeting in RA.