PURPOSE: Hedgehog signaling does not only play crucial roles during development, but has also been implicated in the pathogenesis of several diseases in the adult. The aim of the present study was to investigate the role of the hedgehog pathway for fibroblast activation in systemic sclerosis (SSc). METHODS: The activation of the hedgehog pathway was analyzed by immunohistochemistry and real-time PCR. The effects of sonic hedgehog (Shh) on the collagen synthesis was analyzed by reporter assays, real-time PCR and SirCol assays. Myofibroblast differentiation was assessed by quantification of a-smooth muscle actin (αSMA) and stress fiber staining. The role of hedgehog signaling in vivo was analyzed by adenoviral overexpression of Shh and with mice lacking one allele of the inhibitory receptor Patched-1 (Ptch(+/-) mice). RESULTS: We demonstrate that Shh is overexpressed and results in activation of hedgehog signaling in SSc patients with accumulation of the transcription factors Gli-1 and Gli-2 and increased transcription of hedgehog target genes. Activation of hedgehog signaling induced an activated phenotype in cultured fibroblasts with differentiation of resting fibroblasts into myofibroblasts and increased release of collagen. Adenoviral overexpression of Shh in the skin of mice was sufficient to induce skin fibrosis. Moreover, Ptch(+/-) mice with increased hedgehog signaling were more sensitive to bleomycin induced dermal fibrosis. CONCLUSION: We demonstrate that the hedgehog pathway is activated in SSc patients. Hedgehog signaling potently stimulates the release of collagen and myofibroblast differentiation in vitro and is sufficient to induce fibrosis in vivo. These findings identify the hedgehog cascade as a pro-fibrotic pathway in SSc.