Study of the mechanism of skin fibrosis by utilizing transgenic mice : A mouse scieroderma model

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Systemic sclerosis(SSc)is a multisystem disorder of connective tissue characterized by excessive fibrosis in the skin and various internal organs such as lung, heart, kidney and esophagus.Trans forming growth factor(TGF-β)and connective tissue growth factor(CTGF)have received attention as an essential factor in pathogenesis of SSc.We established an animal model of skin fibrosis by TGF-β injection into subcutaneous tissue of newborn mice and investigated the role of CTGF in skin fibrosis.We utilized transgenic repoter mice harboring the -17kb promoter sequence of the mouse COL1A2 linked to either a firefly luciferase gene or a bacterial b-galactosidase gene.Serial injections of CTGF after TGF-β resulted in a sustained elevation of COL1A2 mRNA expression and promoter activity compared with consecutive injection of TGF-β alone on day 8.We also demonstrated that the number of fibroblasts with activated COL1A2 transcription was increased by serial injections of CTGF after TGF-β in comparison with injection of TGF-β alone.These results suggested that CTGF maintains TGF-β-induced skin fibrosis by sustaining COL1A2 promoter activation and increasing the number of activated fibroblasts.