Article
Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma.
Section of Rheumatology, University of Illinois at Chicago, 60607, USA.
Journal of Investigative Dermatology (impact factor:
6.31).
08/2003;
121(1):41-50.
DOI:10.1046/j.1523-1747.2003.12308.x
pp.41-50
Source: PubMed
-
Citations (0)
- Cited In (4)
-
Article: Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes.
[show abstract] [hide abstract]
ABSTRACT: Connective tissue growth factor (CTGF) is important for transforming growth factor-beta (TGF-beta)-induced liver fibrogenesis. Hepatic stellate cells have been recognized as its major cellular source in the liver. Here we demonstrate the induction of CTGF expression in hepatocytes of damaged livers and identify a molecular mechanism responsible for it. CTGF expression was found by immunohistochemistry in bile duct epithelial cells, hepatic stellate cells, and hepatocytes in fibrotic liver tissue from patients with chronic hepatitis B infection. Similarly, CTGF expression was induced in hepatocytes of carbon tetrachloride-treated mice. CTGF expression and secretion were detected spontaneously in a medium of hepatocytes after 3 days of culture, which was enhanced by stimulation with TGF-beta. TGF-beta-induced CTGF expression was mediated through the activin receptor-like kinase 5 (ALK5)/Smad3 pathway, whereas activin receptor-like kinase 1 activation antagonized this effect. CTGF expression in the liver tissue of TGF-beta transgenic mice correlated with serum TGF-beta levels. Smad7 overexpression in cultured hepatocytes abrogated TGF-beta-dependent and intrinsic CTGF expression, indicating that TGF-beta signaling was required. In line with these data, hepatocyte-specific transgenic Smad7 reduced CTGF expression in carbon tetrachloride-treated animals, whereas in Smad7 knockout mice, it was enhanced. Furthermore, an interferon gamma treatment of patients with chronic hepatitis B virus infection induced Smad7 expression in hepatocytes, leading to decreased CTGF expression and fibrogenesis. CONCLUSION: Our data provide evidence for the profibrogenic activity of TGF-beta directed to hepatocytes and mediated via the up-regulation of CTGF. We identify ALK5-dependent Smad3 signaling as the responsible pathway inducing CTGF expression, which can be hindered by an activated activin receptor-like kinase 1 pathway and completely inhibited by TGF-beta antagonist Smad7.Hepatology 11/2007; 46(4):1257-70. · 11.66 Impact Factor -
Article: 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?
[show abstract] [hide abstract]
ABSTRACT: 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. 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. 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. 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.Arthritis & Rheumatism 02/2009; 60(2):592-603. · 7.87 Impact Factor -
Article: Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma.
[show abstract] [hide abstract]
ABSTRACT: Scleroderma (systemic sclerosis [SSc]), is characterized by progressive multiorgan fibrosis. We recently implicated lysophosphatidic acid (LPA) in the pathogenesis of pulmonary fibrosis. The purpose of the present study was to investigate the roles of LPA and two of its receptors, LPA₁ and LPA₂, in dermal fibrosis in a mouse model of SSc. Wild type (WT), and LPA₁-knockout (KO) and LPA₂-KO mice were injected subcutaneously with bleomycin or phosphate buffered saline (PBS) once daily for 28 days. Dermal thickness, collagen content, and numbers of cells positive for α-smooth muscle actin (α-SMA) or phospho-Smad2 were determined in bleomycin-injected and PBS-injected skin. In separate experiments, a novel selective LPA₁ antagonist AM095 or vehicle alone was administered by oral gavage to C57BL/6 mice that were challenged with 28 daily injections of bleomycin or PBS. AM095 or vehicle treatments were initiated concurrently with, or 7 or 14 days after, the initiation of bleomycin and PBS injections and continued to the end of the experiments. Dermal thickness and collagen content were determined in injected skin. The LPA₁ -KO mice were markedly resistant to bleomycin-induced increases in dermal thickness and collagen content, whereas the LPA₂-KO mice were as susceptible as the WT mice. Bleomycin-induced increases in dermal α-SMA+ and phospho-Smad2+ cells were abrogated in LPA₁-KO mice. Pharmacologic antagonism of LPA₁ with AM095 significantly attenuated bleomycin-induced dermal fibrosis when administered according to either a preventive regimen or two therapeutic regimens. These results suggest that LPA/LPA₁ pathway inhibition has the potential to be an effective new therapeutic strategy for SSc, and that LPA₁ is an attractive pharmacologic target in dermal fibrosis.Arthritis & Rheumatism 01/2011; 63(5):1405-15. · 7.87 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed.
The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual
current impact factor.
Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence
agreement may be applicable.
Keywords
apparent activation
bleomycin injections
dermal cells
fibroblast activation
growth factor-beta responses
growth factor-beta signaling pathway
growth factor-beta-inducible Smad7
growth factor-beta/Smad signaling
growth factor-betain vitro
Infiltrating macrophages
intense staining
murine model
phosphorylated Smad2/3
present studies
progressive fibrosis
relative Smad7 deficiency
selective anti-fibrotic interventions
Smad expression
Smad signaling
Transforming growth factor-beta
