Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis.

Hetal B Patel, Michele Bombardieri, André L F Sampaio, Fulvio D'Acquisto, Mohini Gray, Paolo Grieco, Stephen J Getting, Costantino Pitzalis, Mauro Perretti

William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, UK.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2010 Dec

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The development of biological therapies has improved management of rheumatoid arthritis. However, costs and unresponsiveness to therapy in a sizeable proportion of patients limit their use, making it imperative to identify new targets for drug development programs. Here we investigated the melanocortin-receptor type 3 (MC(3)) pathway. Gene-deficient mice were subjected to a model of serum-transfer-induced arthritis and joints analyzed for gene expression (cytokines, MCs) and morphology. Pharmacological analyses were also conducted in this model. Osteoclastogenesis was studied from bone marrow cells. Mc(3)(-/-) mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Rankl. Osteoclastogenesis studied from Mc(3)(-/-) bone marrow cells revealed a higher degree of responsiveness to Rankl, linked to prolonged NF-κB activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1β, Il-6, and Nos2, was measured in Mc(3)(-/-) mice, and a marked up-regulation of joint Mc(3) accompanied arthritis resolution in wild-type mice. Administration of an MC(3) agonist, D[Trp8]-γ-MSH, attenuated disease incidence and severity in wild-type but not Mc(3)(-/-) mice. Overall, these findings identify MC(3)-mediated signaling as a beneficial pathway in experimental arthritis; hence this receptor is a novel target for the development of therapeutics for arthritis.

Citation

Hetal B Patel, Michele Bombardieri, André L F Sampaio, Fulvio D'Acquisto, Mohini Gray, Paolo Grieco, Stephen J Getting, Costantino Pitzalis, Mauro Perretti. Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2010 Dec;24(12):4835-43