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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)4835-43
Number of pages9
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Issue number12
Publication statusPublished - Dec 2010


  • Animals
  • Arthritis, Experimental
  • Cell Differentiation
  • Electrophoretic Mobility Shift Assay
  • Flow Cytometry
  • Interleukin-1beta
  • Interleukin-6
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type II
  • Oligonucleotide Array Sequence Analysis
  • Osteoclasts
  • Osteogenesis
  • Polymerase Chain Reaction
  • Receptor, Melanocortin, Type 3
  • Journal Article
  • Research Support, Non-U.S. Gov't

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