Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model.
OBJECTIVE
Systemic sclerosis (SSc) is characterized by the fibrosis of various organs, vascular hyperreactivity, and immunologic dysregulation. Since Notch signaling is known to affect fibroblast homeostasis, angiogenesis, and lymphocyte development, we undertook this study to investigate the role of the Notch pathway in human and murine SSc.


METHODS
SSc was induced in BALB/c mice by subcutaneous injections of HOCl every day for 6 weeks. Notch activation was analyzed in tissues from mice with SSc and from patients with scleroderma. Mice with SSc were either treated or not treated with the γ-secretase inhibitor DAPT, a specific inhibitor of the Notch pathway, and the severity of the disease was evaluated.


RESULTS
As previously described, mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase I antibodies. The Notch pathway was hyperactivated in the skin, lung, fibroblasts, and splenocytes of diseased mice and in skin biopsy samples from patients with scleroderma. ADAM-17, a proteinase involved in Notch activation, was overexpressed in the skin of mice and patients in response to the local production of reactive oxygen species. In HOCl-injected mice, DAPT significantly reduced the development of skin and lung fibrosis, decreased skin fibroblast proliferation and ex vivo serum-induced endothelial H(2)O(2) production, and abrogated the production of anti-DNA topoisomerase I antibodies.


CONCLUSIONS
Our results show the pivotal role of the ADAM-17/Notch pathway in SSc following activation by reactive oxygen species. The inhibition of this pathway may represent a new treatment of this life-threatening disease.
Kavian
Niloufar
N
Université Paris Descartes and Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
Servettaz
Amélie
A
Mongaret
Céline
C
Wang
Andrew
A
Nicco
Carole
C
Chéreau
Christiane
C
Grange
Philippe
P
Vuiblet
Vincent
V
Birembaut
Philippe
P
Diebold
Marie-Danièle
MD
Weill
Bernard
B
Dupin
Nicolas
N
Batteux
Frédéric
F
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D018709:Statistics, Nonparametric
D051880:Receptors, Notch; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse