Sunitinib inhibits the phosphorylation of platelet-derived growth factor receptor β in the skin of mice with scleroderma-like features and prevents the development of the disease.
OBJECTIVE
Systemic sclerosis (SSc) is characterized by fibrosis of the skin and visceral organs, vascular dysfunction, and immunologic dysregulation. Platelet-derived growth factors (PDGFs) have been implicated in the development of fibrosis and dysregulation of vascular function. We investigated the effects of sunitinib and sorafenib, two tyrosine kinase inhibitors that interfere with PDGF signaling, in a mouse model of diffuse SSc.


METHODS
SSc was induced in BALB/c mice by subcutaneous injections of HOCl daily for 6 weeks. Mice were randomized to treatment with sunitinib, sorafenib, or vehicle. The levels of native and phosphorylated PDGF receptor β (PDGFRβ) and vascular endothelial growth factor receptor (VEGFR) in the skin were assessed by Western blot and immunohistochemical analyses. Skin and lung fibrosis were evaluated by histologic and biochemical methods. Autoantibodies were detected by enzyme-linked immunosorbent assay, and spleen cell populations were analyzed by flow cytometry.


RESULTS
Phosphorylation of PDGFRβ and VEGFR was higher in fibrotic skin from HOCl-injected mice with SSc than from PBS-injected mice. Injections of HOCl induced cutaneous and lung fibrosis, increased the proliferation rate of fibroblasts in areas of fibrotic skin, increased splenic B cell and T cell counts, and increased anti-DNA topoisomerase I autoantibody levels in BALB/c mice. All of these features were reduced by sunitinib but not by sorafenib. Sunitinib significantly reduced the phosphorylation of both PDGF and VEGF receptors.


CONCLUSIONS
Inhibition of the hyperactivated PDGF and VEGF pathways by sunitinib prevented the development of fibrosis in HOCl-induced murine SSc and may represent a new SSc treatment for testing in clinical trials.
Université Paris Descartes, Hôpital Cochin, AP-HP, Paris, France.
Niloufar
N
Kavian
Amélie
A
Servettaz
Wioleta
W
Marut
Carole
C
Nicco
Christiane
C
Chéreau
Bernard
B
Weill
Frédéric
F
Batteux
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077210:Sunitinib
D007211:Indoles; D011758:Pyrroles; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib