Rac inhibition reverses the phenotype of fibrotic fibroblasts.
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.
Xu
Shi-wen
SW
Centre for Rheumatology, Department of Medicine, University College London (Royal Free Campus), London, United Kingdom.
Liu
Shangxi
S
Eastwood
Mark
M
Sonnylal
Sonali
S
Denton
Christopher P
CP
Abraham
David J
DJ
Leask
Andrew
A
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*
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