Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis
Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis
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DOI：
10.1096/fj.10-167759
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发表时间：
2010-12-01
期刊：
影响因子：
4.8
通讯作者：
Perretti, Mauro
中科院分区：
文献类型：
--
作者：
Patel, Hetal B.;Bombardieri, Michele;Perretti, Mauro
生物疗法的发展改善了类风湿性关节炎的治疗。然而，相当大一部分患者的成本和对治疗的无反应限制了它们的使用，因此迫切需要为药物开发计划确定新的靶点。在这里，我们研究了黑素皮质素受体3型(MC3)途径。基因缺陷小鼠受到血清转移诱导的关节炎模型和关节的基因表达(细胞因子)和形态分析。在该模型中还进行了药理分析。对骨髓细胞进行破骨细胞分化的研究。MC(3)(-/-)小鼠表现为炎性关节炎加重，伴有明显的骨质侵蚀和关节RANKL的高表达。从Mc(3)(-/-)骨髓细胞进行的破骨细胞分化研究表明，与野生型相比，RANKL对RANKL的反应程度更高，与核因子-kappaB的激活时间延长有关。在Mc(3)(-/-)小鼠中，检测到一组离散的炎症基因，包括IL-1β、IL-6和NOS2的上调，在野生型小鼠中，关节Mc(3)的显著上调伴随着关节炎的消退。给予MC3激动剂D[Trp8]-Gamma-MSH可以减轻野生型小鼠的发病率和严重程度，但不能减轻Mc(3)(-/)-小鼠的疾病发病率和严重程度。总体而言，这些发现确认MC3介导的信号是实验性关节炎的有益途径；因此，这种受体是开发关节炎疗法的新目标。-Patel，H.B.，Bombardieri，M.，Sampaio，A.L.F.，D‘Acquisto，F.，Gray，M.，Grieco，P.，Ging，S.J.，Pitzalis，C.，Perretti，M.内源性黑素皮质素受体3型在实验性关节炎中的抗炎和抗破骨作用。FASE B J.24,4835-4843(2010)。Www.fasebj.org
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