Fli1

Abstract

Systemic sclerosis (SSc) is a multifactorial connective tissue disease caused by the complex interplay between genetic factors and environmental influences. Fli1, a member of Ets transcription factor family, is constitutively suppressed in various cell types in the lesional and non-lesional skin of SSc patients at least partially by an epigenetic mechanism. Therefore, Fli1 deficiency is a potential predisposing factor of SSc reflecting environmental influences. Consistent with this notion, Fli1+/- mice reproduce SSc-like phenotypes in dermal fibroblasts and dermal microvascular endothelial cells at molecular levels. Importantly, bleomycin, a potential environmental factor of SSc, induces more prominent SSc-like phenotypes in various cell types of Fli1+/- mice than in those of wildtype mice. Furthermore, endothelial cell-specific Fli1 knockout mice reproduce the functional and structural vascular abnormalities characteristic of SSc vasculopathy. Moreover, double heterozygous mice for Fli1 and Klf5, another transcription factor epigenetically suppressed in SSc dermal fibroblasts, spontaneously develop three cardinal features of SSc including immune abnormalities, vasculopathy, and tissue fibrosis of the skin and lung. Thus, Fli1 deficiency is a key feature in the pathogenesis of SSc. On the other hand, accumulating evidence has suggested that Fli1 is a potential therapeutic target of SSc because Fli1 expression can be reversed by bosentan, a dual endothelin receptor antagonist with a preventive effect on digital ulcers relevant to SSc. Therefore, the studies on the role of Fli1 in SSc provide us new clues to further understand the pathogenesis of SSc and to develop a new therapeutic strategy for this devastating and incurable disease.