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Abstract

Objective

Recently, we found that human dermal fibroblasts (HDFs) express melanocortin 1 receptors (MC-1R) that bind α-melanocyte–stimulating hormone (α-MSH). In search of novel therapies for scleroderma (systemic sclerosis [SSc]), we used the bleomycin (BLM) model to investigate the effects of α-MSH on collagen synthesis and fibrosis.

Methods

Collagen expression in HDFs was determined by real-time reverse transcription–polymerase chain reaction (RT-PCR) and Western blot analyses. Signal transduction studies included pharmacologic blockade, immunofluorescence analysis, Western blotting, and reporter–promoter assays. Oxidative stress was measured by fluorescence-activated cell sorter analysis, and anti–oxidative enzyme levels were determined by real-time RT-PCR and Western blot analyses. The effect of α-MSH in the BLM mouse model of scleroderma was assessed by histologic, immunohistochemical, real-time RT-PCR, and protein analyses. Expression of MC-1R and pro-opiomelanocortin (POMC) in skin and HDF samples from patients with SSc was determined by RT-PCR and compared with that in samples from normal controls.

Results

Treatment with α-MSH (and related peptides) suppressed BLM-induced expression of type I and type III collagen in HDFs, and this effect was cAMP-dependent. Neither BLM nor α-MSH altered Smad signaling, but antioxidants inhibited BLM-induced collagen expression in vitro. In addition, α-MSH suppressed BLM-induced oxidative stress and enhanced the expression of superoxide dismutase 2 (SOD2) and heme oxygenase 1 (HO-1). In the BLM mouse model, α-MSH reduced skin fibrosis and collagen content and increased tissue levels of SOD2 and HO-1. In skin and HDFs from patients with SSc, both MC-1R and POMC messenger RNAs were detected, but there were no differences compared with healthy controls.

Conclusion

Alpha-melanocyte–stimulating hormone and related peptides that exert their effects via MC-1R may provide a novel antifibrogenic therapeutic tool for the treatment of fibrotic diseases such as scleroderma.