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.
