TY - JOUR
T1 - Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts
T2 - a potential treatment for Graves' ophthalmopathy
AU - van Steensel, Leendert
AU - Paridaens, Dion
AU - Schrijver, Benjamin
AU - Dingjan, Gemma M
AU - van Daele, Paul L A
AU - van Hagen, P Martin
AU - van den Bosch, Willem A
AU - Drexhage, Hemmo A
AU - Hooijkaas, Herbert
AU - Dik, Willem A
PY - 2009/7
Y1 - 2009/7
N2 - PURPOSE: 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.
AB - PURPOSE: 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Becaplermin
KW - Benzamides
KW - Cell Proliferation/drug effects
KW - Cells, Cultured
KW - Female
KW - Fibroblasts/metabolism
KW - Gene Expression Regulation/physiology
KW - Glucuronosyltransferase/genetics
KW - Graves Ophthalmopathy/drug therapy
KW - Humans
KW - Hyaluronan Synthases
KW - Hyaluronic Acid/biosynthesis
KW - Imatinib Mesylate
KW - Male
KW - Middle Aged
KW - Orbit/metabolism
KW - Phosphorylation
KW - Piperazines/pharmacology
KW - Platelet-Derived Growth Factor/antagonists & inhibitors
KW - Polymerase Chain Reaction
KW - Protein Kinase Inhibitors/pharmacology
KW - Protein-Tyrosine Kinases/antagonists & inhibitors
KW - Proto-Oncogene Proteins c-abl/metabolism
KW - Proto-Oncogene Proteins c-sis/genetics
KW - Pyrimidines/pharmacology
KW - RNA, Messenger/metabolism
KW - Receptors, Platelet-Derived Growth Factor/metabolism
KW - Signal Transduction/drug effects
KW - Transforming Growth Factor beta1/genetics
U2 - 10.1167/iovs.08-2443
DO - 10.1167/iovs.08-2443
M3 - Article
C2 - 19234339
VL - 50
SP - 3091
EP - 3098
IS - 7
ER -