Recent advances in animal models of systemic sclerosis.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by the three cardinal pathological features, comprising aberrant immune activation, vasculopathy and tissue fibrosis, with unknown etiology. Although many inducible and genetic animal models mimicking the selected aspects of SSc have been well documented, the lack of models encompassing the full clinical manifestations hindered the development and preclinical testing of therapies against this disease. Under this situation, three new genetic animal models have recently been established, such as Fra2 transgenic mice, urokinase-type plasminogen activator receptor deficient mice and Klf5(+/-) ;Fli1(+/-) mice, all of which recapitulate the pathological cascade of SSc. The former two murine models demonstrate endothelial cell apoptosis and capillary loss followed by tissue fibrosis, whereas the immune systems show no remarkable abnormality. Klf5(+/-) ;Fli1(+/-) mice develop immune activation, vasculopathy and tissue fibrosis in this sequence, eventually resulting in the development of dermal fibrosis, interstitial lung disease and pulmonary vascular involvement resembling those of SSc. Because Krueppel-like factor (KLF)5 and Friend leukemia integration 1 transcription factor (Fli1) are the transcription factors epigenetically suppressed in SSc dermal fibroblasts, the reproduction of SSc manifestations in Klf5(+/-) ;Fli1(+/-) mice supports the canonical idea that environmental influences play a central role in the development of SSc in genetically predisposed individuals. These new animal models offer important clues for the better understanding of the underlying molecular mechanisms of SSc pathology and the identification of potential molecular targets for the treatment of this incurable disease.