Imatinib Mesylate and AMN107 Inhibit PDGF-Signaling in Orbital Fibroblasts: A Potential Treatment for Graves' Ophthalmopathy
| Autor: | Willem A. Dik, Benjamin Schrijver, P. Martin van Hagen, Dion Paridaens, Willem A. van den Bosch, Herbert Hooijkaas, Leendert van Steensel, Gemma M. Dingjan, Hemmo A. Drexhage, Paul L A van Daele |
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| Přispěvatelé: | Immunology, Ophthalmology, Internal Medicine |
| Rok vydání: | 2009 |
| Předmět: |
Male
Becaplermin Polymerase Chain Reaction Piperazines Medicine Receptors Platelet-Derived Growth Factor Glucuronosyltransferase Hyaluronic Acid Phosphorylation Proto-Oncogene Proteins c-abl Cells Cultured Aged 80 and over Platelet-Derived Growth Factor biology Proto-Oncogene Proteins c-sis Middle Aged Protein-Tyrosine Kinases Hyaluronan synthase medicine.anatomical_structure Benzamides Imatinib Mesylate Female Orbit Tyrosine kinase Platelet-derived growth factor receptor Signal Transduction medicine.drug Adult medicine.medical_specialty Transforming Growth Factor beta1 Internal medicine Humans RNA Messenger Kinase activity Fibroblast Protein Kinase Inhibitors Aged Cell Proliferation business.industry Imatinib Fibroblasts eye diseases Graves Ophthalmopathy Pyrimidines Imatinib mesylate Endocrinology Gene Expression Regulation Nilotinib Cancer research biology.protein business Hyaluronan Synthases |
| Zdroj: | Investigative Ophthalmology & Visual Science, 50(7), 3091-3098. Association for Research in Vision and Ophthalmology Inc. |
| ISSN: | 1552-5783 0146-0404 3091-3098 |
| Popis: | 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-BB and TGF-beta(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. (Invest Ophthalmol Vis Sci. 2009;50:3091-3098) DOI:10.1167/iovs.08-2443 |
| Databáze: | OpenAIRE |
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