title: Rac inhibition reverses the phenotype of fibrotic fibroblasts.
abstract: BACKGROUND
  Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrix and produce alpha-smooth muscle actin (alpha-SMA), type I collagen and CCN2 (connective tissue growth factor, CTGF). The basis for this phenomenon is poorly understood, and is a necessary prerequisite for developing novel, rational anti-fibrotic strategies.
  
  
  RESULTS
  Compared to healthy skin fibroblasts, dermal fibroblasts cultured from lesional areas of scleroderma (SSc) patients possess elevated Rac activity. NSC23766, a Rac inhibitor, suppressed the persistent fibrotic phenotype of lesional SSc fibroblasts. NSC23766 caused a decrease in migration on and contraction of matrix, and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. SSc fibroblasts possessed elevated Akt phosphorylation, which was also blocked by NSC23766. Overexpression of rac1 in normal fibroblasts induced matrix contraction and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. Rac1 activity was blocked by PI3kinase/Akt inhibition. Basal fibroblast activity was not affected by NSC23766.
  
  
  CONCLUSIONS
  Rac inhibition may be considered as a novel treatment for the fibrosis observed in SSc.
authors.affiliation: Centre for Rheumatology, Department of Medicine, University College London (Royal Free Campus), London, United Kingdom.
authors.forename: Shi-wen
authors.initials: SW
authors.lastname: Xu
authors.forename: Shangxi
authors.initials: S
authors.lastname: Liu
authors.forename: Mark
authors.initials: M
authors.lastname: Eastwood
authors.forename: Sonali
authors.initials: S
authors.lastname: Sonnylal
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
mesh_terms: D000199:Actins / Q000378:metabolism*; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D009130:Muscle, Smooth / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000199:Actins; C526317:CCN2 protein, human; C107953:RAC1 protein, human; D055513:Connective Tissue Growth Factor; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein