title: 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.
authors.affiliation: Graduate School of Medical Science, Saga Medical School, Saga, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Sherriff-Tadano
authors.forename: Akihide
authors.initials: A
authors.lastname: Ohta
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Morito
authors.forename: Mio
authors.initials: M
authors.lastname: Mitamura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Haruta
authors.forename: Shuichi
authors.initials: S
authors.lastname: Koarada
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Tada
authors.forename: Kohei
authors.initials: K
authors.lastname: Nagasawa
authors.forename: Iwata
authors.initials: I
authors.lastname: Ozaki
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045743:Scleroderma, Diffuse / Q000473:pathology*; D045745:Scleroderma, Limited / Q000473:pathology*; D012867:Skin / Q000473:pathology*
chemical_list: D019138:Antibodies, Blocking; C526317:CCN2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016207:Cytokines; C494041:ETS1 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor; D017228:Hepatocyte Growth Factor; D003094:Collagen; D020781:Matrix Metalloproteinase 1