Presented by Dr. Kokot in partial fulfillment of the requirements for a PhD degree, University of Münster, Münster, Germany.
α-melanocyte–stimulating hormone suppresses bleomycin-induced collagen synthesis and reduces tissue fibrosis in a mouse model of scleroderma: Melanocortin peptides as a novel treatment strategy for scleroderma?
Article first published online: 29 JAN 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 2, pages 592–603, February 2009
How to Cite
Kokot, A., Sindrilaru, A., Schiller, M., Sunderkötter, C., Kerkhoff, C., Eckes, B., Scharffetter-Kochanek, K., Luger, T. A. and Böhm, M. (2009), α-melanocyte–stimulating hormone suppresses bleomycin-induced collagen synthesis and reduces tissue fibrosis in a mouse model of scleroderma: Melanocortin peptides as a novel treatment strategy for scleroderma?. Arthritis & Rheumatism, 60: 592–603. doi: 10.1002/art.24228
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- Manuscript Accepted: 3 OCT 2008
- Manuscript Received: 6 JAN 2008
- Deutsche Forschungsgemeinschaft. Grant Numbers: SFB497, P7, EC140/5-1, BO 1075/5-3
- Deutsches Netzwerk Systemische Sklerodermie. Grant Number: DLR/BMBF 01 GM 0310
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.
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.
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.
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.