Dr. O. Distler has received consulting fees from Actelion, Pfizer, Ergonex, Bristol-Myers Squibb, Sanofi-Aventis, United BioSource, Medac, Swedish Orphan Biovitrum, Novartis, 4D Sciences, and Active Biotec (less than $10,000 each).
Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis
Article first published online: 27 JUL 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 8, pages 2724–2733, August 2012
How to Cite
Horn, A., Palumbo, K., Cordazzo, C., Dees, C., Akhmetshina, A., Tomcik, M., Zerr, P., Avouac, J., Gusinde, J., Zwerina, J., Roudaut, H., Traiffort, E., Ruat, M., Distler, O., Schett, G. and Distler, J. H. W. (2012), Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis & Rheumatism, 64: 2724–2733. doi: 10.1002/art.34444
- Issue published online: 27 JUL 2012
- Article first published online: 27 JUL 2012
- Accepted manuscript online: 21 FEB 2012 03:01PM EST
- Manuscript Accepted: 14 FEB 2012
- Manuscript Received: 2 JUN 2011
- Deutsche Forschungsgesellschaft. Grant Numbers: DI 1537/2-1, DI 1537/4-1, AK 144/1-1, SCHE 1583/7-1
- Interdisciplinary Center of Clinical Research
- Erlangen. Grant Numbers: IZKF grant A20, CMH Research Project 00000023728
- DFG (Immunobone program)
Hedgehog signaling not only plays crucial roles during human development but also has been implicated in the pathogenesis of several diseases in adults. The aim of the present study was to investigate the role of the hedgehog pathway in fibroblast activation in systemic sclerosis (SSc).
Activation of the hedgehog pathway was analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). The effects of sonic hedgehog (SHH) on collagen synthesis were analyzed by reporter assays, real-time PCR, and Sircol assays. Myofibroblast differentiation was assessed by quantification of α-smooth muscle actin and stress fiber staining. The role of hedgehog signaling in vivo was analyzed by adenoviral overexpression of SHH and using mice lacking 1 allele of the gene for inhibitory receptor Patched homolog 1 (Ptch+/− mice).
SHH was overexpressed and resulted in activation of hedgehog signaling in patients with SSc, 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.
We demonstrated that the hedgehog pathway is activated in patients with SSc. 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 profibrotic pathway in SSc.