title: Sirt1 regulates canonical TGF-β signalling to control fibroblast activation and tissue fibrosis.
abstract: BACKGROUND
  Sirt1 is a member of the sirtuin family of proteins. Sirt1 is a class III histone deacetylase with important regulatory roles in transcription, cellular differentiation, proliferation and metabolism. As aberrant epigenetic modifications have been linked to the pathogenesis of systemic sclerosis (SSc), we aimed to investigate the role of Sirt1 in fibroblast activation.
  
  
  METHODS
  Sirt1 expression was analysed by real-time PCR, western blot and immunohistochemistry. Sirt1 signalling was modulated with the Sirt1 agonist resveratrol and by fibroblast-specific knockout. The role of Sirt1 was evaluated in bleomycin-induced skin fibrosis and in mice overexpressing a constitutively active transforming growth fac-tor-β (TGF-β) receptor I (TBRIact).
  
  
  RESULTS
  The expression of Sirt1 was decreased in patients with SSc and in experimental fibrosis in a TGF-β-dependent manner. Activation of Sirt1 potentiated the profibrotic effects of TGF-β with increased Smad reporter activity, elevated transcription of TGF-β target genes and enhanced release of collagen. In contrast, knockdown of Sirt1 inhibited TGF-β/SMAD signalling and reduced release of collagen in fibroblasts. Consistently, mice with fibroblast-specific knockdown of Sirt1 were less susceptible to bleomycin- or TBRIact-induced fibrosis.
  
  
  CONCLUSIONS
  We identified Sirt1 as a crucial regulator of TGF-β/Smad signalling in SSc. Although Sirt1 is downregulated, this decrease is not sufficient to counterbalance the excessive activation of TGF-β signalling in SSc. However, augmentation of this endogenous regulatory mechanism, for example, by knockdown of Sirt1, can effectively inhibit TGF-β signalling and exerts potent antifibrotic effects. Sirt1 may thus be a key regulator of fibroblast activation in SSc.
authors.affiliation: Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.affiliation: Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.affiliation: Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jingang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.affiliation: Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Sumova
authors.affiliation: Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001761:Bleomycin; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000502:physiology*; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta; D001761:Bleomycin; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Fibroblasts; Systemic Sclerosis; Treatment