Contribution of activin receptor-like kinase 5 (transforming growth factor beta receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts.
OBJECTIVE
To use a specific transforming growth factor beta receptor type I (TGFbetaRI; activin receptor-like kinase 5 [ALK-5]) kinase inhibitor (SD208) to determine the role of activation of the TGFbetaRI kinase (ALK-5) in maintaining the profibrotic phenotype of dermal fibroblasts in systemic sclerosis (SSc).


METHODS
The effect of SD208 on the expression of key biochemical markers of the fibrotic phenotype was compared in fibroblasts cultured from clinically involved (lesional) and clinically uninvolved skin of patients with diffuse cutaneous SSc (dcSSc) and in fibroblasts from healthy controls matched for age, sex, and anatomic site. Protein expression was compared together with the ability of fibroblasts to adhere to the extracellular matrix and to remodel and contract a free-floating fibroblast-populated type I collagen lattice.


RESULTS
Inhibiting TGFbetaRI kinase reduced the expression of a cohort of fibrotic markers by dermal fibroblasts from patients with dcSSc, including type I collagen and beta1 integrin. Moreover, inhibition also attenuated the elevated adhesive and contractile abilities of dcSSc fibroblasts.


CONCLUSIONS
Our data suggest that some of the key profibrotic features of lesional SSc fibroblasts are dependent upon ALK-5 activity. Thus, TGFbetaRI kinase-mediated signaling may contribute to dermal fibrosis in dcSSc.
Royal Free and University College Medical School, London, UK.
Yunliang
Y
Chen
Xu
X
Shi-wen
Mark
M
Eastwood
Carol M
CM
Black
Christopher P
CP
Denton
Andrew
A
Leask
David J
DJ
Abraham
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D045743:Scleroderma, Diffuse / Q000235:genetics*; D015398:Signal Transduction
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human