alpha-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?
OBJECTIVE
Recently, we found that human dermal fibroblasts (HDFs) express melanocortin 1 receptors (MC-1R) that bind alpha-melanocyte-stimulating hormone (alpha-MSH). In search of novel therapies for scleroderma (systemic sclerosis [SSc]), we used the bleomycin (BLM) model to investigate the effects of alpha-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 alpha-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 alpha-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 alpha-MSH altered Smad signaling, but antioxidants inhibited BLM-induced collagen expression in vitro. In addition, alpha-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, alpha-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.


CONCLUSIONS
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.
Kokot
Agatha
A
University of Münster, Münster, Germany.
Sindrilaru
Anca
A
Schiller
Meinhard
M
Sunderkötter
Cord
C
Kerkhoff
Claus
C
Eckes
Beate
B
Scharffetter-Kochanek
Karin
K
Luger
Thomas A
TA
Böhm
Markus
M
D000328:Adult; D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D020405:Dermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004336:Drug Antagonism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000521:alpha-MSH / Q000494:pharmacology* / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D006728:Hormones; D012333:RNA, Messenger; D044101:Receptors, Melanocortin; D001761:Bleomycin; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D003094:Collagen; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase