Systemic sclerosis (SSc) is a
chronic disease of unknown etiology that is characterized by multiple tissue
fibrosis.
Transforming Growth Factor-beta (TGF-β) is thought to be the most important mediator that induces
fibrosis. However, the molecular mechanisms by which
fibrosis is induced have not been fully elucidated. In this study, the role of
activin, a member of the TGF-β superfamily, was investigated in the pathogenesis of
fibrosis in SSc. Serum
activin A levels in patients with SSc were measured by ELISA, and the expression of the
activin receptor type IB (ACVRIB/ALK4) and the activity of the signaling pathway via ACVRIB/ALK4 were investigated using western blotting. To evaluate a potential therapeutic strategy for SSc, we also attenuated the ACVRIB/ALK4 pathway using an inhibitor. Serum
activin A levels were significantly higher in SSc patients than in normal controls.
Activin A and ACVRIB/ALK4 expression were also higher in cultured SSc fibroblasts.
Activin A stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts.
Procollagen production and Col1α
mRNA also increased upon stimulation by
activin A. The basal level of Smad2/3 phosphorylation was higher in cultured SSc fibroblasts than in control cells, and treatment with the ALK4/5 inhibitor
SB431542 prevented phosphorylation of Smad2/3 and CTGF expression. Furthermore, production of
collagen was also induced by
activin A. Activin A-ACVRIB/ALK4-Smad-dependent
collagen production was augmented in SSc fibroblasts, suggesting the involvement of this signaling mechanism in SSc. Inhibition of the
activin A-ACVRIB/ALK4-Smad pathway would be a new approach for the treatment of SSc.