Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis.
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.
Patel
Hetal B
HB
William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, UK.
Bombardieri
Michele
M
Sampaio
André L F
AL
D'Acquisto
Fulvio
F
Gray
Mohini
M
Grieco
Paolo
P
Getting
Stephen J
SJ
Pitzalis
Costantino
C
Perretti
Mauro
M
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics / Q000378:metabolism*
D053583:Interleukin-1beta; D015850:Interleukin-6; D044104:Receptor, Melanocortin, Type 3; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse