title: Metformin reduces TGF-β1-induced extracellular matrix production in nasal polyp-derived fibroblasts.
abstract: BACKGROUND AND OBJECTS: Metformin is widely used to treat type 2 diabetes mellitus, and adenosine monophosphate-activated protein kinase (AMPK) is thought to be the target that mediates its effects. Recently, it has been demonstrated that metformin has antifibrotic effects beyond its antihyperglycemic action. The purposes of this study were to investigate the effect of metformin on TGF-β1-induced myofibroblast differentiation (α-smooth muscle actin [α-SMA]) and extracellular matrix (ECM) production and to determine the underlying mechanism of the action of metformin in nasal polyp-derived fibroblasts (NPDFs).
  
  
  METHODS
  Basic research.
  
  
  METHODS
  The rhinology laboratory of Korea University Guro Hospital, Seoul, Korea.
  
  
  METHODS
  NPDFs from 7 patients were incubated with TGF-β1 and treated with metformin or compound C, an inhibitor of AMPK. To determine the proliferation rate of nasal fibroblasts, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed. The expression levels of α-SMA and fibronectin were determined by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescent staining. Phosphorylation of AMPK and phosphorylation of Smad2/3 were evaluated by Western blot analysis.
  
  
  RESULTS
  In TGF-β1-induced NPDFs, metformin inhibited the expression of α-SMA and fibronectin, as confirmed by both RT-PCR and Western blot analysis. Metformin increased the phosphorylation of AMPK and the expression levels of α-SMA and fibronectin. However, compound C reversed these effects. Metformin inhibited TGF-β1-induced phosphorylation of Smad2/3.
  
  
  CONCLUSIONS
  This study showed that metformin inhibits TGF-β1-induced myofibroblast differentiation and ECM production in NPDFs via the Smad2/3 pathway. AMPK can be a therapeutic target for the prevention of ECM remodeling in nasal polyps.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea.
authors.forename: Il-Ho
authors.initials: IH
authors.lastname: Park
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Um
authors.forename: Sung-Moon
authors.initials: SM
authors.lastname: Hong
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Cho
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Sang Hag
authors.initials: SH
authors.lastname: Lee
authors.forename: Heung-Man
authors.initials: HM
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000199:Actins / Q000032:analysis; D000328:Adult; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D005353:Fibronectins / Q000032:analysis; D005455:Fluorescent Antibody Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D058628:Myofibroblasts / Q000000981:diagnostic imaging*; D009298:Nasal Polyps / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D014463:Ultrasonography
chemical_list: D000199:Actins; D005353:Fibronectins; D007004:Hypoglycemic Agents; D053773:Transforming Growth Factor beta1; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: adenosine monophosphate–activated protein kinase; fibroblast; fibronectin; metformin; nasal polyposis