Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis
- Resource Type
- Authors
- Martial Ruat; Christian Beyer; Oliver Distler; Angelika Horn; Trayana Kireva; Cinzia Cordazzo; Michal Tomcik; Alfiya Akhmetshina; Clara Dees; Georg Schett; Katrin Palumbo-Zerr; Pawel Zerr; Jörg H W Distler
- Source
- Annals of the Rheumatic Diseases
Annals of the Rheumatic Diseases, BMJ Publishing Group, 2012, epub ahead of print. ⟨10.1136/annrheumdis-2011-200883⟩
- Subject
- Small interfering RNA
2745 Rheumatology
Receptors, G-Protein-Coupled
Mice
chemistry.chemical_compound
0302 clinical medicine
Medizinische Fakultät
Fibrosis
Immunology and Allergy
Medicine
RNA, Small Interfering
Skin
0303 health sciences
integumentary system
10051 Rheumatology Clinic and Institute of Physical Medicine
Smoothened Receptor
Hedgehog signaling pathway
3. Good health
2723 Immunology and Allergy
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Drug Therapy, Combination
Myofibroblast
Signal Transduction
Immunology
610 Medicine & health
Bleomycin
Skin Diseases
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Rheumatology
1300 General Biochemistry, Genetics and Molecular Biology
Animals
ddc:610
Hedgehog
030304 developmental biology
030203 arthritis & rheumatology
2403 Immunology
Scleroderma, Systemic
business.industry
Biphenyl Compounds
medicine.disease
Mice, Mutant Strains
Mice, Inbred C57BL
Disease Models, Animal
chemistry
Cancer research
business
Smoothened
- Language
- ISSN
- 1468-2060
0003-4967
ObjectivesTissue fibrosis is a leading cause of death in patients with systemic sclerosis (SSc). Effective antifibrotic treatments are not available. Here, the authors investigated inhibition of hedgehog signalling by targeting Smoothened (Smo) as a novel antifibrotic approach.MethodsThe activation status of the hedgehog pathway was assessed by immunohistochemistry for Gli transcription factors and by quantification 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 fibrosis and in tight-skin-1 mice.ResultsHedgehog 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, myofibroblast differentiation and accumulation of collagen upon challenge with bleomycin. Targeting Smo also exerted potent antifibrotic effects in tight-skin-1 mice and did prevent progression of fibrosis and induced regression of pre-established fibrosis.ConclusionsInhibition of hedgehog signalling exerted potent antifibrotic effects in preclinical models of SSc in both preventive and therapeutic settings. These findings might have direct translational implications because inhibitors of Smo are already available and yielded promising results in initial clinical trials.