Alpha-MSH suppresses collagen synthesis

Suppression of collagen synthesis is a major therapeutic goal in treatment of fibrotic disorders. We show here that alpha-melanocyte-stimulating hormone (alpha-MSH), a neuropeptide well known for its pigment-inducing capacity, modulates collagen synthesis and deposition. AlphaMSH in vitro suppresses the synthesis of collagen type I, III and V and down-regulates the secretion of procollagen type I C-terminal peptide (PICP) in human dermal fibroblasts treated with the fibrogenic cytokine transforming growth factor-beta1 (TGF-beta1). Alpha-MSH did not interfere with TGF-beta1 signaling since TGF-beta1-induced expression of collagen mRNA was not affected implying a posttranscriptional mechanism. Human dermal fibroblasts in vitro express high-affinity binding sites for MSH which were identified by RT-PCR and immunofluorescence analysis as the melanocortin-1 receptor (MC-1R). Immunohistochemical studies on normal adult human skin confirmed MC-1R expression in distinct dermal fibroblastic cells. The MC-1R on fibroblasts appears functionally relevant since alpha-MSH increased intracellular cAMP and coincubation with a synthetic peptide corresponding to human Agouti signaling protein abrogated the inhibition of TGF-beta1-induced PICP secretion by alpha-MSH. To assess the in vivo relevance of these findings, a mouse model was used in which dermal fibrosis was induced by repetitive intracutaneous injections with TGF-beta1. The inductive activity of TGF-beta1 on collagen deposition and number of dermal cells immunoreactive for vimentin and alpha-smooth muscle actin was significantly suppressed by injection of alpha-MSH. Melanocortins such as alpha-MSH may therefore represent a novel class of modulators with potential usefulness for treatment of fibrotic disorders. by gest on A uust 7, 2017 hp://w w w .jb.org/ D ow nladed from Alpha-MSH suppresses collagen synthesis 3