Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves' ophthalmopathy.
OBJECTIVE
Excessive orbital fibroblast proliferation and hyaluronan production are characteristic of Graves' ophthalmopathy (GO) and are driven by local mediators. Imatinib mesylate and AMN107 are tyrosine kinase inhibitors that inhibit fibroblast proliferation and collagen production in lungs and skin. This study was conducted to determine whether imatinib mesylate and AMN107 inhibit orbital fibroblast proliferation and hyaluronan production induced by PDGF-BB and TGF-beta(1) and whether expression of the genes PDGF-B and TGF-B(1) (growth factors suggested to play a role in GO) are increased in GO orbital tissues.


METHODS
PDGF-B and TGF-B(1) mRNA levels were determined in orbital tissues of 13 patients with GO and 5 control patients. Orbital fibroblasts were cultured from eight patients with GO and three control patients and the effect of imatinib mesylate and AMN107 on PDGF-BB and TGF-beta(1)-induced orbital fibroblast proliferation, signaling cascades, hyaluronan synthase (HAS) gene expression and hyaluronan production were determined.


RESULTS
PDGF-B and TGF-B(1) mRNA levels were significantly increased in GO orbital tissues. Imatinib mesylate and AMN107 inhibited PDGF-BB-induced orbital fibroblast proliferation, HAS induction and hyaluronan production by blocking PDGF-receptor phosphorylation. TGF-beta(1) induced HAS expression and hyaluronan production. This induction was not inhibited by imatinib mesylate or AMN107, due to the inability of TGF-beta(1) to activate c-Abl kinase activity in orbital fibroblasts.


CONCLUSIONS
Imatinib mesylate and AMN107 inhibit orbital fibroblast proliferation and hyaluronan production induced by PDGF-BB; a factor highly expressed in orbital tissue from patients with GO. The drugs, however, had no effect on TGF-beta(1)-induced HAS expression and hyaluronan production. Nevertheless, imatinib mesylate and AMN107 should be considered as treatment candidates for GO.
van Steensel
Leendert
L
Departments of Immunology and.
Paridaens
Dion
D
Schrijver
Benjamin
B
Dingjan
Gemma M
GM
van Daele
Paul L A
PL
van Hagen
P Martin
PM
van den Bosch
Willem A
WA
Drexhage
Hemmo A
HA
Hooijkaas
Herbert
H
Dik
Willem A
WA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077214:Becaplermin; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D014453:Glucuronosyltransferase / Q000235:genetics; D049970:Graves Ophthalmopathy / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009915:Orbit / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000494:pharmacology
D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib