Anti‐inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis
| Autor: | Mohini Gray, Costantino Pitzalis, André L. F. Sampaio, Mauro Perretti, Paolo Grieco, Stephen J. Getting, Fulvio D'Acquisto, Michele Bombardieri, Hetal B. Patel |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
medicine.medical_specialty medicine.drug_class Inflammatory arthritis Interleukin-1beta Nitric Oxide Synthase Type II Osteoclasts Arthritis Electrophoretic Mobility Shift Assay Polymerase Chain Reaction Biochemistry Mice Melanocortin receptor Osteogenesis Internal medicine medicine Genetics Animals Receptor Molecular Biology Oligonucleotide Array Sequence Analysis Mice Knockout biology Interleukin-6 business.industry Cell Differentiation Flow Cytometry medicine.disease Arthritis Experimental Mice Inbred C57BL Endocrinology medicine.anatomical_structure RANKL Rheumatoid arthritis biology.protein Cancer research Bone marrow business Receptor Melanocortin Type 3 Biotechnology |
| Zdroj: | The FASEB Journal. 24:4835-4843 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.10.167759 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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