title: Effect of SMAD7 gene overexpression on TGF-β1-induced profibrotic responses in fibroblasts derived from Peyronie's plaque.
abstract: Transforming growth factor-β1 (TGF-β1) has been identified as one of the most important fibrogenic cytokines associated with Peyronie's disease (PD). The mothers against decapentaplegic homolog 7 (SMAD7) is an inhibitory Smad protein that blocks TGF-β signaling pathway. The aim of this study was to examine the anti-fibrotic effect of the SMAD7 gene in primary fibroblasts derived from human PD plaques. PD fibroblasts were pretreated with the SMAD7 gene and then stimulated with TGF-β1. Treated fibroblasts were used for Western blotting, fluorescent immunocytochemistry, hydroxyproline determination, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. Overexpression of the SMAD7 gene inhibited TGF-β1-induced phosphorylation and nuclear translocation of SMAD2 and SMAD3, transdifferentiation of fibroblasts into myofibroblasts, and quashed TGF-β1-induced production of extracellular matrix protein and hydroxyproline. Overexpression of the SMAD7 gene decreased the expression of cyclin D1 (a positive cell cycle regulator) and induced the expression of poly (ADP-ribose) polymerase 1, which is known to terminate Smad-mediated transcription, in PD fibroblasts. These findings suggest that the blocking of the TGF-β pathway by use of SMAD7 may be a promising therapeutic strategy for the treatment of PD.
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Choi
authors.forename: Kang-Moon
authors.initials: KM
authors.lastname: Song
authors.forename: Jin-Mi
authors.initials: JM
authors.lastname: Park
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Kwon
authors.forename: Ki-Dong
authors.initials: KD
authors.lastname: Kwon
authors.forename: Soo-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Dong-Soo
authors.initials: DS
authors.lastname: Ryu
authors.forename: Ji-Kan
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: Department of Urology, National Research Center for Sexual Medicine, Inha University School of Medicine, Incheon 400-711, Korea.
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Suh
mesh_terms: D002478:Cells, Cultured; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology*; D005355:Fibrosis / Q000139:chemically induced; D006801:Humans; D006909:Hydroxyproline / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010411:Penile Induration / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051906:Smad7 Protein / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D019938:Cyclin D1; D011065:Poly(ADP-ribose) Polymerases; D006909:Hydroxyproline