Skhirtladze C et al. – Src kinases play important roles in the activation of fibroblasts and in the development of experimental fibrosis. Thus, Src kinases might be interesting targets for novel antifibrotic therapies in SSc. Methods
Study to evaluate the potential of Src kinases as novel targets of antifibrotic therapies
Fibroblast cultures were obtained from 10 SSc pts and 5 healthy subjects
Src signaling was inhibited using small-molecule inhibitors and overexpression of a dominant-negative mutant of Src and of the endogenous inhibitor Csk
The expression of extracellular matrix proteins was analyzed by RT-PCR and by SirCol collagen assay
Toxic effects were excluded by MTT assay and staining for annexin V and propidium iodide
The mouse model of bleomycin-induced dermal fibrosis was used to assess the role of Src kinases in dermal fibrosis in vivo
Results
Stimulation with TGF-β and PDGF activated Src signaling in dermal fibroblasts from pts with SSc and healthy donors
Incubation with the Src kinase inhibitors or overexpressed mutant Src or Csk reduced the synthesis of mRNA for COL1A1, COL1A2, and fibronectin 1
A dose-dependent reduction in collagen release was also observed at the protein level
No inhibitory effects on proliferation and no increase in the number of apoptotic or necrotic fibroblasts were observed
Consistent with the in vitro data, inhibition of Src kinases prevented experimental dermal fibrosis
Dermal thickness, the amount of collagen protein, and the no. of myofibroblasts were reduced in a dose-dependent manner
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