Chondroprotective role of the melanocortin system in osteoarthritis

黑素皮质激素（MCs）最初被定义为神经激素，具有广泛的作用。然而，我们目前对黑素皮质素系统在软骨中的功能的认识是稀缺的。最近，我们发现黑色素皮质素-1受体（MC-1R）在人软骨细胞中表达。α-促黑素细胞激素（α-MSH）是MCs的一种原型，能够调节一些参与软骨细胞细胞外基质组成和炎症的基因。例如，α-MSH可减弱白细胞介素(IL)-1β诱导的基质金属蛋白酶(MMP)-1、-2、-9、-13以及IL-6、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-1R在骨关节炎（OA）中的作用。(1)巩固α-MSH对OA关键效应细胞的体外抗炎保护作用。(2)我们将确定α-MSH在这些细胞中的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)研究结果的相关性将在人体软骨移植模型中进行评估。(4)最后，我们将在建立的小鼠OA模型中检测α-MSH和去甲肾上腺素的疗效。(5)通过MC-1R信号缺失小鼠，这些实验也将阐明MC-1R是否在内源性软骨保护中发挥作用。这些研究可能为骨性关节炎等退行性关节疾病的神经内分泌治疗开辟新的途径。

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.