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

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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.