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- Title
Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis.
- Authors
Patel, Hetal B.; Bombardieri, Michele; Sampaio, Andre L. F.; D'Acquisto, Fulvio; Gray, Mohini; Grieco, Paolo; Getting, Stephen J.; Pitzalis, Costantino; Perretti, Mauro
- 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 ardiritis 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(Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed.) mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Ranhl. Osteoclastogenesis studied from Mc(Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed.) bone marrow cells revealed a higher degree of responsiveness to Rankl, linked to prolonged NF-Κ activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1βIl-6, 11-6, and Nos2, was measured in Mc(Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed.) 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 Mc(Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed.) 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.
- Subjects
BIOLOGICAL research; G protein coupled receptors; OSTEOCLASTS; CYTOKINES; TREATMENT of arthritis
- Publication
FASEB Journal, 2010, Vol 24, Issue 12, p4835
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.10-167759