title: Focal adhesion kinase and reactive oxygen species contribute to the persistent fibrotic phenotype of lesional scleroderma fibroblasts.
abstract: OBJECTIVE
  Fibrotic diseases such as SSc (systemic sclerosis, scleroderma) are characterized by the abnormal presence of the myofibroblast, a specialized type of fibroblast that overexpresses the highly contractile protein α-smooth muscle actin. Myofibroblasts display excessive adhesive properties and hence exert a potent mechanical force. We aim to identify the precise contribution of adhesive signalling, which requires integrin-mediated activation of focal adhesion kinase (FAK)/src, to fibrogenic gene expression in normal and fibrotic SSc fibroblasts.
  
  
  METHODS
  We subject either FAK wild-type and knockout fibroblasts or normal and SSc fibroblasts treated with FAK/src inhibitors to real-time polymerase chain, western blot, cell migration and collagen gel contraction analyses.
  
  
  RESULTS
  FAK operates downstream of both integrin β1 and reactive oxygen species (ROS) to promote the expression of genes involved in matrix production and remodelling, including CCN2, α-smooth muscle actin and type I collagen. Blocking either FAK/src with PP2 or ROS with N-acetyl cysteine alleviates the elevated contractile and migratory capability of lesional SSc dermal fibroblasts.
  
  
  CONCLUSIONS
  Excessive adhesive signalling is intimately involved with the fibrotic phenotype of lesional SSc fibroblasts; blocking adhesive signalling or ROS generation may be beneficial in controlling the fibrosis observed in SSc.
authors.affiliation: Centre for Rheumatology, University College London (Royal Free Campus), London, UK.
authors.forename: Xu
authors.initials: X
authors.lastname: Shi-wen
authors.forename: Katherine
authors.initials: K
authors.lastname: Thompson
authors.forename: Korsa
authors.initials: K
authors.lastname: Khan
authors.forename: Shangxi
authors.initials: S
authors.lastname: Liu
authors.forename: Hannah
authors.initials: H
authors.lastname: Murphy-Marshman
authors.forename: Murray
authors.initials: M
authors.lastname: Baron
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D058628:Myofibroblasts / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000209:etiology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C412373:AG 1879; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051416:Focal Adhesion Protein-Tyrosine Kinases