A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in model mice of systemic sclerosis (50.31)

Abstract

Abstract Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc). TGF-β is well known to be the principal factor that leads to tissue fibrosis. We tested a novel small compound HSc025, which is an antagonist of TGF-β/Smads signaling, would prevent tissue fibrosis in vitro or in mouse models of SSc. Human dermal fibroblasts were exposed at various doses of HSc025 in the presence of TGF-β, and the expression levels of collagen or fibronectin were determined. Administration of HSc025 (15 mg/kg/day, p.o.), halofuginone (1μg/mouse/day, i.p.) or placebo to tight skin mouse or to bleomycin-induced pulmonary fibrosis mice was performed for 14 days. Pretreatment with HSc025 prevented Smad-dependent promoter activation in a dose-dependent manner, however, HSc025 had no effect on TGF-β-induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGF-β-induced collagen or fibronectin expression were also confirmed in vitro. The oral administration of HSc025 dramatically reduced hypodermal thickness in tight skin mice, and markedly decreased hydroxyproline contents and histological score in the lungs of bleomycine-treated mice. These results demonstrate that HSc025 is a novel inhibitor against TGF-β/Smads signaling, resulting in the improvement of skin and pulmonary fibrosis. Therefore, orally available HSc025 might be useful for the therapy of SSc.