Role of alpha-Melanocyte-Stimulating-Hormone (MSH) in senescence/ageing of skin and cartilage

黑素皮质素系统是人体重要的神经内分泌调节单位。对于黑素皮质素肽，特别是α - msh，我们和其他人报道了通过发挥免疫调节作用抑制炎症和衰老相关过程的皮肤和骨/软骨保护特性。在目前的项目中，我们重点分析了α - msh对两种不同间充质组织：皮肤和软骨的衰老相关作用。软骨是一种只有最小的内在再生能力的组织，而皮肤具有很高的再生能力。确定两种组织中常见的α - msh分子效应/信号通路，将有助于更好地理解对氧化应激和衰老相关功能丧失等长期组织有害影响的可能共同反应。在这里，我们的目标是解决以下目标：我们希望在衰老和衰老的原型诱变剂的背景下，定义α - msh介导的关节软骨细胞和真皮成纤维细胞衰老过程中的信号通路和潜在的分子机制，并描述MC1R信号受损对体外两种细胞类型的细胞衰老的影响。通过uva照射的MC1R信号缺陷个体皮肤外植体和老年MC1R信号缺陷小鼠（Mc1re/e）或手术诱导骨关节炎（一种与年龄相关的滑膜关节疾病）Mc1re/e小鼠的关节软骨的体外分析，将揭示α - msh /MC1R信号通路和调节间充质组织结构和功能的机制。最终，α - msh可能通过MC1R信号支持组织免受氧化应激的保护，氧化应激促进细胞衰老和年龄相关疾病。我们的共同努力将产生更多新的分子知识，了解α - msh /MC1R信号在年龄相关过程中的关键作用，最终阻碍组织完整性和正常功能。了解两种不同间充质组织中α - msh抗氧化特性的潜在分子机制和信号通路，将为预防或延缓影响身体所有组织的年龄相关疾病开辟新的途径。

The melanocortin system is an important neuroendocrine regulator unit within the body. For melanocortin peptides, specifically alpha-MSH, we and others reported dermal- and osteo/chondro-protective properties by exerting immunomodulatory effects dampening inflammatory and ageing-related processes. For the present project, we focus on analysing senescence associated effects of alpha-MSH on two different mesenchymal tissues: skin and cartilage. Cartilage is a tissue with only minimal intrinsic regenerative capacity whereas skin has a high regenerative capacity. Determination of molecular alpha-MSH effects/signalling pathways, which are common for both tissues will lead to a better general understanding of possible common responses to long term tissue-detrimental influences as oxidative stress and ageing related loss of function. Here, we aim to address following goals: We want to define the signalling pathways and underlying molecular mechanisms of alpha-MSH mediated effects on ageing processes in articular chondrocytes and dermal fibroblasts in the context of prototypical inducers of aging and senescence and to delineate the impact of impaired MC1R signaling on cellular senescence in both cell types in vitro. Ex vivo analysis of UVA-irradiated skin explants from MC1R-signaling-deficient individuals and articular cartilage from either aged MC1R-signaling deficient (Mc1re/e) mice or Mc1re/e mice with surgically induced Osteoarthritis (an age related synovial joint disease), shall reveal those alpha-MSH/MC1R signalling pathways and mechanisms which modulate mesenchymal tissue structure and function. Ultimately, alpha-MSH may support protection of tissues via MC1R signalling from oxidative stress, which promotes cellular senescence and age-related disorders. Our combined efforts will generate additional novel molecular knowledge on the critical role of alpha-MSH/MC1R signalling for age-related processes eventually hampering tissue integrity and proper function. Understanding the underlying molecular mechanisms and signalling pathways responsible for the anti-oxidative properties of alpha-MSH in two different mesenchymal tissues will open up new avenues for preventing or delaying age-related disorders affecting all tissues in the body.