title: Growth Differentiation Factor-9 Promotes Fibroblast Proliferation and Migration in Keloids through the Smad2/3 Pathway.
abstract: BACKGROUND
  Keloids are fibroproliferative scars that develop as a result of a dysregulated wound healing process; however, the molecular mechanisms of keloid pathogenesis remain unclear. Keloids are characterized by the ability to spread beyond the original boundary of the wound, and they represent a significant clinical challenge. Previous work from our group suggested that growth differentiation factor (GDF)-9 plays a role in the invasive behavior of keloids. Here, we examined the involvement of GDF-9 in keloid formation and spread and elucidated a potential underlying mechanism.
  
  
  METHODS
  The expression of GDF-9, cyclooxygenase (COX)-2, vascular epidermal growth factor (VEGF)-C, matrix metalloprotease (MMP)-2, MMP-9, transforming growth factor (TGF)-β1, and the related signaling pathway components in human keloid tissues or keloid fibroblasts (kFBs) was monitored by qRT-PCR and western blot. A series of overexpression and silencing experiments in normal and keloid fibroblasts were used to modify the expression of GDF-9. The effects of GDF-9 on kFB proliferation and migration were assessed using the CCK-8, cell cycle and scratch wound healing assays.
  
  
  RESULTS
  GDF-9 promotes fibroblast proliferation and migration. GDF-9 silencing in kFBs decreased cell proliferation, blocked cell cycle progression, downregulated the angiogenic markers COX-2 and VEGF-C, and downregulated MMP-2 and MMP-9 expression, whereas it had no effect on the levels of TGF-β1. GDF-9 silencing significantly inhibited Smad2 and Smad3 phosphorylation in kFBs.
  
  
  CONCLUSIONS
  GDF-9 promotes the proliferation and migration of kFBs via a mechanism involving the Smad2/3 pathway.
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Jiang
authors.forename: Qingxiong
authors.initials: Q
authors.lastname: Yu
authors.forename: Lingling
authors.initials: L
authors.lastname: Xia
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000328:Adult; D002465:Cell Movement; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D020868:Gene Silencing; D055429:Growth Differentiation Factor 9 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007627:Keloid / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C525897:GDF9 protein, human; D055429:Growth Differentiation Factor 9; D051899:Smad2 Protein; D051900:Smad3 Protein; D042582:Vascular Endothelial Growth Factor C; D051546:Cyclooxygenase 2