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

Patel, Hetal B. and Bombardieri, Michele and Sampaio, André L.F. and D'Acquisto, Fulvio and Gray, Mohini and Grieco, Paolo and Getting, Stephen J. and Pitzalis, Costantino and Perretti, Mauro (2010) Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis. FASEB Journal, 24 (12). pp. 4835-4843. ISSN 0892-6638

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Official URL: http://dx.doi.org/10.1096/fj.10-167759

Abstract

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 (MC3) 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. Mc3−/− mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Rankl. Osteoclastogenesis studied from Mc3−/− 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 Mc3−/− mice, and a marked up-regulation of joint Mc3 accompanied arthritis resolution in wild-type mice. Administration of an MC3 agonist, D[Trp8]-γ-MSH, attenuated disease incidence and severity in wild-type but not Mc3−/− mice. Overall, these findings identify MC3-mediated signaling as a beneficial pathway in experimental arthritis; hence this receptor is a novel target for the development of therapeutics for arthritis.—Patel, H. B., Bombardieri, M., Sampaio, A. L. F., D'Acquisto, F., Gray, M., Grieco, P., Getting, S. J., Pitzalis, C., Perretti, M. Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:9017
Deposited On:20 Jan 2011 11:38
Last Modified:20 Jan 2011 11:38

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