TY - JOUR
T1 - Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis
AU - Patel, Hetal B.
AU - Bombardieri, Michele
AU - Sampaio, Andre L. F.
AU - D'Acquisto, Fulvio
AU - Gray, Mohini
AU - Grieco, Paolo
AU - Getting, Stephen J.
AU - Pitzalis, Costantino
AU - Perretti, Mauro
PY - 2010/12
Y1 - 2010/12
N2 - 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. 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-kappa B activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1 beta, 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 MC3 agonist, D[Trp8]-gamma-MSH, attenuated disease incidence and severity in wild-type but not Mc(3)(-/)- 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. FASEB J. 24, 4835-4843 (2010). www.fasebj.org
AB - 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. 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-kappa B activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1 beta, 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 MC3 agonist, D[Trp8]-gamma-MSH, attenuated disease incidence and severity in wild-type but not Mc(3)(-/)- 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. FASEB J. 24, 4835-4843 (2010). www.fasebj.org
UR - http://www.scopus.com/inward/record.url?scp=78649749715&partnerID=8YFLogxK
U2 - 10.1096/fj.10-167759
DO - 10.1096/fj.10-167759
M3 - Article
SN - 0892-6638
VL - 24
SP - 4835
EP - 4843
JO - The FASEB Journal
JF - The FASEB Journal
IS - 12
ER -