title: NADPH Oxidase 4 Mediates TGFβ1-induced CCN2 in Gingival Fibroblasts.
abstract: Transforming growth factor β (TGFβ) plays a central role in the pathogenesis of gingival overgrowth (GO). Connective tissue growth factor (CTGF; or CCN2) is induced by TGFβ in human gingival fibroblasts (HGFs) and is overexpressed in GO tissues. CCN2 creates an environment favorable for fibrogenesis and is required for the maximal profibrotic effects of TGFβ. We previously showed that Src, JNK, and Smad3 mediate TGFβ1-induced CCN2 protein expression in HGFs. Moreover, Src is an upstream signaling transducer of JNK and Smad3. Recent studies suggested that NADPH oxidase (NOX)-dependent redox mechanisms are involved in mediating the profibrotic effects of TGFβ. In this study, we demonstrated that TGFβ1 upregulated NOX4 protein expression and increased reactive oxygen species (ROS) production in HGFs. Genetic or pharmacologic targeting of NOX4 abrogated TGFβ1-induced ROS production; Src, JNK, and Smad3 activation; and CCN2 and type I collagen protein expression in HGFs. Our results indicated that NOX4-derived ROS play pivotal roles in activating Src kinase activity leading to the activation of canonical (Smad3) and noncanonical (JNK) cascades that cooperate to attain maximum CCN2 expression. Furthermore, we demonstrated that curcumin significantly inhibited the TGFβ1-induced NOX4 protein expression in HGFs. Curcumin potentially qualifies as an agent to control GO by suppressing TGFβ1-induced NOX4 expression in HGFs.
authors: School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: W H
authors: WH
authors: Yang
authors: Department of Dentistry, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan.
authors: Y T
authors: YT
authors: Deng
authors: School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Y P
authors: YP
authors: Hsieh
authors: Department of Dentistry, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan.
authors: K J
authors: KJ
authors: Wu
authors: School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan oddie@ntu.edu.tw.
authors: M Y P
authors: MY
authors: Kuo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000502:physiology*; D003474:Curcumin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D020868:Gene Silencing; D005881:Gingiva / Q000166:cytology* / Q000201:enzymology; D019214:Gingival Overgrowth / Q000201:enzymology / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009285:Naphthoquinones / Q000494:pharmacology; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism; D013481:Superoxides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C526317:CCN2 protein, human; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009285:Naphthoquinones; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D013481:Superoxides; D055513:Connective Tissue Growth Factor; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D019061:src-Family Kinases; D003474:Curcumin; D000111:Acetylcysteine; C014758:plumbagin
keywords: chemoprevention; curcumin; fibrosis; gingival overgrowth; reactive oxygen species; signal transduction