Overexpression of hepatocyte growth factor receptor in scleroderma dermal fibroblasts is caused by autocrine transforming growth factor β signaling.
Cutaneous fibrosis seen in systemic sclerosis (SSc) is caused by fibroblast activation and abnormal collagen accumulation due to 'autocrine transforming growth factor (TGF)-β/Smad signaling'. Hepatocyte growth factor (HGF) may have therapeutic value against SSc, because of its inducible effect on the expression of matrix metalloproteinase (MMP)-1. Previous studies indicated SSc dermal fibroblasts overexpress HGF receptor c-met, which suggest specific and effective induction of MMP-1 in SSc fibroblasts caused by HGF treatment. However, the exact mechanism of c-met overexpression in SSc cells was hardly investigated. We hypothesized that such c-met overexpression is also caused by autocrine TGF-β/Smad signaling. Expression of c-met protein in cultured SSc dermal fibroblasts was significantly up-regulated compared with that in normal fibroblasts. Ectopic TGF-β stimulation induced c-met synthesis in normal fibroblasts, while a TGF-β knockdown normalized the up-regulated c-met levels in SSc fibroblasts. Furthermore, we found the c-met promoter contains a putative binding site for Smads, and the binding activity of Smad2/3 to the c-met promoter was constitutively up-regulated in SSc fibroblasts as well as in normal fibroblasts treated with exogenous TGF-β1. Taken together, c-met may be overexpressed due to autocrine TGF-β/Smad signaling in SSc. Considering that HGF has an antifibrotic effect, such c-met overexpression in SSc fibroblasts may be a negative feedback against cutaneous fibrosis. Clarifying the mechanisms of c-met overexpression and controlling the HGF/c-met pathway may lead to a new therapeutic approach for this disease.
Department of Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan.
I
I
Kajihara
M
M
Jinnin
T
T
Makino
S
S
Masuguchi
K
K
Sakai
S
S
Fukushima
K
K
Maruo
Y
Y
Inoue
H
H
Ihn
D019898:Autocrine Communication / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D009841:Oligonucleotides / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000150:complications* / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000473:pathology*; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D009841:Oligonucleotides; D016212:Transforming Growth Factor beta; D019859:Proto-Oncogene Proteins c-met