Collagen Metabolism Is a Novel Target of the Neuropeptide α-Melanocyte-stimulating Hormone

Abstract

Suppression of collagen synthesis is a major therapeutic goal in the treatment of fibrotic disorders. We show here that α -melanocyte-stimulating hormone (α-MSH), a neuropeptide well known for its pigment-inducing capacity, modulates collagen synthesis and deposition. α-MSH in vitro suppresses the synthesis of collagen types 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-β1 (TGF-β1). α-MSH did not interfere with TGF-β1 signaling, because TGF-β 1-induced expression of collagen mRNA was not affected, implying a posttranscriptional mechanism. Human dermal fibroblasts in vitro express a high affinity binding site for MSH, which was identified by reverse transcription 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 to be functionally relevant because α-MSH increased the amount of intracellular cAMP, and coincubation with a synthetic peptide corresponding to the human Agouti signaling protein abrogated the inhibition of TGF-β 1-induced PICP secretion by α-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-β 1. The inductive activity of TGF-β1 on collagen deposition and the number of dermal cells immunoreactive for vimentin and α-smooth muscle actin was significantly suppressed by injection of α-MSH. Melanocortins such as α-MSH may therefore represent a novel class of modulators with potential usefulness for the treatment of fibrotic disorders.