A unifying hypothesis for the pathogenesis of systemic sclerosis based on the deficiency of transcription factor Fli1: The development of a new animal model of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a multisystem connective tissue disease featured by immune abnormalities, vasculopathy and resultant fibrosis of the skin and various internal organs. Although the pathogenesis of SSc remains incompletely elucidated, it is currently accepted that this disease is caused by the complex interplay between hereditary and environmental factors. The deficiency of transcription factor Fli1, which is epigenetically suppressed in SSc dermal fibroblasts, potentially causes SSc-like phenotypical alteration in various cell types such as fibroblasts, endothelial cells, and macrophages, suggesting that Fli1 is a predisposing factor of SSc. KLF5 is another transcription factor which is suppressed in SSc dermal fibroblasts through an epigenetic mechanism. Importantly, double heterozygous mice for Fli1 and KLF5 develop three cardinal features of SSc, including immune abnormalities, vasculopathy and fibrosis. Therefore, these two transcription factors are likely to be critical predisposing factors regulating the development of SSc. Given that potential disease modifying drugs, bosentan and imatinib, reverse the expression and transcriptional activity of Fli1, the studies on the pathological process of double heterozygous mice and the impact of these transcription factors on various cell types may provide a new clue to further understand the pathogene-sis of SSc leading to the development of new therapies.