Combined inhibition of morphogen pathways demonstrates additive antifibrotic effects and improved tolerability.
OBJECTIVE
The morphogen pathways Hedgehog, Wnt and Notch are attractive targets for antifibrotic therapies in systemic sclerosis. Interference with stem cell regeneration, however, may complicate the use of morphogen pathway inhibitors. We therefore tested the hypothesis that combination therapies with low doses of Hedgehog, Wnt and Notch inhibitors maybe safe and effective for the treatment of fibrosis.


METHODS
Skin fibrosis was induced by bleomycin and by overexpression of a constitutively active TGF-β receptor type I. Adverse events were assessed by clinical monitoring, pathological evaluation and quantification of Lgr5-positive intestinal stem cells.


RESULTS
Inhibition of Hedgehog, Wnt and Notch signalling dose-dependently ameliorated bleomycin-induced and active TGF-β receptor type I-induced fibrosis. Combination therapies with low doses of Hedgehog/Wnt inhibitors or Hedgehog/Notch inhibitors demonstrated additive antifibrotic effects in preventive as well as in therapeutic regimes. Combination therapies were well tolerated. In contrast with high dose monotherapies, combination therapies did not reduce the number of Lgr5 positive intestinal stem cells.


CONCLUSIONS
Combined inhibition of morphogen pathways exerts additive antifibrotic effects. Combination therapies are well tolerated and, in contrast to high dose monotherapies, may not impair stem cell renewal. Combined targeting of morphogen pathways may thus help to overcome dose-limiting toxicity of Hedgehog, Wnt and Notch signalling.
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
Alfiya
A
Distler
Veronika
V
Lang
Tina
T
Del Vecchio
Jingang
J
Huang
Yun
Y
Zhang
Christian
C
Beyer
Neng-Yu
NY
Lin
Katrin
K
Palumbo-Zerr
Oliver
O
Distler
Georg
G
Schett
Jörg Hw
JH
Distler
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001761:Bleomycin; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005355:Fibrosis / Q000188:drug therapy*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011744:Pyrimidinones / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012595:Scleroderma, Systemic / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects*; D014704:Veratrum Alkaloids / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects
D019086:Bridged Bicyclo Compounds, Heterocyclic; D053823:Hedgehog Proteins; C492448:ICG 001; D011744:Pyrimidinones; D051880:Receptors, Notch; D018125:Receptors, Transforming Growth Factor beta; D014704:Veratrum Alkaloids; D051153:Wnt Proteins; D001761:Bleomycin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D053829:Amyloid Precursor Protein Secretases; C000541:cyclopamine
Fibroblasts; Systemic Sclerosis; Treatment