Double heterozygous mice for Klf5 and Fli1 genes: a new animal model of systemic sclerosis recapitulating its three cardinal pathological features.

The lack of animal models recapitulating the three cardinal features of systemic sclerosis (SSc), such as immune activation, vasculopathy, and tissue fibrosis, hinders the understanding of the pathogenesis of this disease. A series of clinical studies has suggested that environmental factors largely contribute to the development of SSc in individuals predisposed by genetic factors. This notion is supported by the establishment of a new murine SSc model which recapitulates three cardinal features of SSc by simultaneous haploinsufficiency of Klf5 and Fli1 genes, both of which are epigenetically suppressed in SSc dermal fibroblasts. In addition to enhanced dermal thickness, Klf5(+/-) and Fli1(+/-) mice resemble dermal fibrosis of SSc at the ultrastructural level. Furthermore, these mice simulate altered vascular structure and B cell activation characteristic of SSc. Further studies on the pathological events in Klf5(+/-) and Fli1(+/-) mice and the roles of KLF5 and Fli1 in various types of cells may provide us with a useful clue to better understand the developmental process of SSc.