Chondroprotective role of the melanocortin system in osteoarthritis

黑皮质素（MCs）最初被定义为神经激素，表现出广泛的作用。然而，我们目前对软骨中黑皮质素系统的功能的了解是稀缺的。最近，我们证明黑皮质素-1受体（MC-1 R）在人软骨细胞中表达。α-促黑素细胞激素（α-Melanocyte-stimulating hormone，α-MSH）是MC的原型，能够调节软骨细胞中参与细胞外基质组成和炎症的许多基因。例如，在一个示例中，α-MSH减弱白细胞介素（IL）-1β诱导的这些细胞中基质金属蛋白酶（MMP）-1、-2、-9和-13以及IL-6和IL-8的表达。基于这些发现，我们认为α-MSH在软骨生理学中具有软骨保护作用。因此，本项目的主要目标是确定α-MSH和MC-1 R在骨关节炎（OA）中的作用。(1)我们将巩固α-MSH在OA关键效应细胞中的抑制和保护作用。(2)我们将确定在这些细胞中介导α-MSH作用的信号通路和分子机制，并将其与使用类似信号通路的去甲肾上腺素进行比较。(3)将在人软骨外植体模型中评估结果的相关性。(4)最后，我们将在已建立的小鼠OA模型中测试α-MSH和去甲肾上腺素的功效。(5)通过使用MC-1 R信号缺陷小鼠，这些实验也将阐明MC-1 R是否在内源性软骨保护中发挥作用。这些研究可能为退行性关节疾病（如OA）的神经内分泌治疗开辟新途径。

Originally defined as neurohormones, melanocortins (MCs) exhibit a wide spectrum of effects. However, our present knowledge on the function of the melanocortin system in cartilage is scarce. Recently, we demonstrated that melanocortin-1 receptor (MC-1R) is expressed in human chondrocytes. α-Melanocyte-stimulating hormone (α-MSH), a prototype of MCs, is capable of regulating a number of genes involved in extracellular matrix composition and inflammation in chondrocytes. E.g., α-MSH attenuates interleukin (IL)-1β-induced expression of matrix metalloproteinases (MMP)-1, -2, -9 and -13 as well as IL-6 and IL-8 in these cells. Based on these findings, we suggest a chondroprotective role of α-MSH in cartilage physiology. Accordingly, the major goal of this project is to define the role of α-MSH and the MC-1R in the context of osteoarthritis (OA). (1) We will consolidate the antiinflammatory and protective in vitro effects of α-MSH in key effector cells of OA. (2) We will identify the signaling pathways and molecular mechanisms mediating the effects of α-MSH in these cells, and we will compare it with norepinephrine that uses similar signaling pathways. (3) The relevance of the findings will be assessed in a human cartilage explant model. (4) Finally, we will test efficacy of α-MSH and norepinephrine in an established murine OA model. (5) By using MC-1R signaling-deficient mice, these experiments will also clarify whether MC- 1R plays a role in endogenous chondroprotection. These investigations may open up novel avenues for the neuroendocrine treatment of degenerative joint diseases like OA.