ORIGINAL ARTICLE
Antifibrotic effects of hepatocyte growth factor on scleroderma fibroblasts and analysis of its mechanism
Authors
Ryoko Sherriff-Tadano1, Akihide Ohta2, Fumitaka Morito3, Mio Mitamura3, Yoshio Haruta3, Shuichi Koarada3, Yoshifumi Tada3, Kohei Nagasawa3 and Iwata Ozaki4
| (1) |
Graduate School of Medical Science, Saga Medical School, Saga, Japan |
| (2) |
Department of Adult and Gerontological Nursing, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan |
| (3) |
Division of Rheumatology, Department of Internal Medicine, Saga Medical School, Saga, Japan |
| (4) |
Health Administration Center, Saga Medical School, Saga, Japan |
Received:
July 13, 2006
Accepted:
August 28, 2006
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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 procollagenα1(I) and connective tissue growth factor (CTGF) in SSc fibroblasts. Expression of transforming growth factor (TGF)-β1 was not inhibited significantly in SSc or control fibroblasts. Hepatocyte growth factor also increased interferon (IFN)-γ 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-γ levels rather than the effect on TGF-β1. The present study indicates that HGF may be a promising therapeutic agent for this intractable disease.
Key words
Collagen, Connective tissue growth factor, Hepatocyte growth factor, Matrix metalloproteinase-1, Scleroderma
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