Inhibition of hedgehog signalling preventsexperimental fibrosis and induces regression ofestablished fibrosis

Objectives Tissue fi brosis is a leading cause of death in patients with systemic sclerosis (SSc). Effective antifi brotic treatments are not available. Here, the authors investigated inhibition of hedgehog signalling by targeting Smoothened (Smo) as a novel antifi brotic approach. Methods The activation status of the hedgehog pathway was assessed by immunohistochemistry for Gli transcription factors and by quantifi cation of hedgehog target genes. Hedgehog signalling was inhibited by the selective inhibitor LDE223 and by small interfering RNA against Smo in the models of bleomycin-induced dermal fi brosis and in tight-skin-1 mice. Results Hedgehog signalling is activated in SSc and in murine models of SSc. Inhibition of Smo either by LDE223 or by small interfering RNA prevented dermal thickening, myofi broblast differentiation and accumulation of collagen upon challenge with bleomycin. Targeting Smo also exerted potent antifi brotic effects in tight-skin-1 mice and did prevent progression of fi brosis and induced regression of pre-established fi brosis. Conclusions Inhibition of hedgehog signalling exerted potent antifi brotic effects in preclinical models of SSc in both preventive and therapeutic settings. These fi ndings might have direct translational implications because inhibitors of Smo are already available and yielded promising results in initial clinical trials.