Antifibrotic effects of hepatocyte growth factor on scleroderma fibroblasts and analysis of its mechanism

Abstract

We investigated the effect of hepatocyte growth factor (HGF) on collagen metabolism in cultured fibroblasts from scleroderma (SSc) patients and discussed the possible mechanism of its effect. Synthesis of matrix metalloproteinase-1 (MMP-1) and collagen and mRNA levels of various cytokines were examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. Hepatocyte growth factor enhanced MMP-1 production and mRNA levels of MMP-1 and Ets-1 (a transcriptional factor of MMPs). In addition, HGF suppressed collagen synthesis and mRNA levels of procollagenalpha1(I) and connective tissue growth factor (CTGF) in SSc fibroblasts. Expression of transforming growth factor (TGF)-beta1 was not inhibited significantly in SSc or control fibroblasts. Hepatocyte growth factor also increased interferon (IFN)-gamma mRNA significantly in SSc and control fibroblasts. Addition of anti-HGF antibody neutralized these effects of HGF on MMP-1 and collagen synthesis. The results suggest that HGF can suppress collagen accumulation in SSc fibroblasts by increasing MMP-1 levels possibly via activation of Ets-1 and also by decreasing collagen synthesis, which may be partly related to inhibition of CTGF, and increasing IFN-gamma levels rather than the effect on TGF-beta1. The present study indicates that HGF may be a promising therapeutic agent for this intractable disease.

Down‐regulation of collagen and connective tissue growth factor expression with hepatocyte growth factor in lung fibroblasts from white scleroderma patients via two signaling pathways

“…Basal expression and activity of MMP-1 in SSc lung fibroblasts is reduced compared with that of normal fibroblasts (26). It has been reported that HGF induces expression and activity of MMP-1 in SSc skin fibroblasts (20,21). To examine whether HGF affects MMP-1 expression in SSc lung fibroblasts, we incubated cells with various concentrations of HGF (5-500 ng/ml) for 72 hours.…”

“…Over the past several years, progress has been made in identifying the cellular targets of HGF and in unraveling the molecular mechanisms that underlie its action in tissue fibrosis (13,14,16,17,21). The biologic effects of HGF are mediated by a membrane-spanning c-Met tyrosine kinase receptor (29).…”

“…Wu et al reported that HGF prevented and ameliorated the symptoms of dermal sclerosis in a mouse model of SSc (19). Several recent studies have characterized antifibrotic effects of HGF on collagen, matrix metalloproteinase 1 (MMP-1), and CTGF in SSc skin fibroblasts (20,21), but the mechanisms underlying its antifibrotic effects in human lung fibroblasts remain to be clarified.…”

Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: Possible role in systemic sclerosis

“…HGF has been shown to attenuate CTGF expression and collagen accumulation in several murine models of fibrosis (23,35). Recently, several groups of investigators reported that HGF inhibits collagen and CTGF production in skin fibroblasts from SSc patients (14,36,37). To establish whether recombinant HGF affects the accumulation of collagen and CTGF in human lung fibroblasts in the same way as in skin fibroblasts, we measured collagen and CTGF expression in lung fibroblasts isolated from Caucasian and African American SSc patients.…”

Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

“…Ets-1 is activated in VSMCs by a variety of stimuli including platelet-derived growth factor-BB, interleukin-1, and tumor necrosis factor-␣ (14,30,48,60). Increased expression of various proteases that degrade the ECM was reported in Ets-1-overexpressing cells (7,16,20,51,54). However, the involvement of Ets-1 in EGF-induced MMP-1 and -9 expressions in carotid plaque VSMCs are not known.…”