Contribution of activin receptor–like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts

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Abstract
Objective To use a specific transforming growth factor β receptor type I (TGFβRI; activin receptor–like kinase 5 [ALK‐5]) kinase inhibitor (SD208) to determine the role of activation of the TGFβRI 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 TGFβRI kinase reduced the expression of a cohort of fibrotic markers by dermal fibroblasts from patients with dcSSc, including type I collagen and β1 integrin. Moreover, inhibition also attenuated the elevated adhesive and contractile abilities of dcSSc fibroblasts. Conclusion Our data suggest that some of the key profibrotic features of lesional SSc fibroblasts are dependent upon ALK‐5 activity. Thus, TGFβRI kinase–mediated signaling may contribute to dermal fibrosis in dcSSc.