In:
Arthritis & Rheumatism, Wiley, Vol. 60, No. 2 ( 2009-02), p. 592-603
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0004-3591
,
1529-0131
Language:
English
Publisher:
Wiley
Publication Date:
2009
detail.hit.zdb_id:
2014367-9
detail.hit.zdb_id:
127294-9
Permalink