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Originally published In Press as doi:10.1167/iovs.08-2443 on February 21, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:3091-3098.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-2443
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Imatinib Mesylate and AMN107 Inhibit PDGF-Signaling in Orbital Fibroblasts: A Potential Treatment for Graves’ Ophthalmopathy

Leendert van Steensel,1 Dion Paridaens,2 Benjamin Schrijver,1 Gemma M. Dingjan,1 Paul L. A. van Daele,1,3 P. Martin van Hagen,1,2,3 Willem A. van den Bosch,2 Hemmo A. Drexhage,1 Herbert Hooijkaas,1 and Willem A. Dik1

1From the Departments of Immunology and 3Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; and the 2Rotterdam Eye Hospital, Rotterdam, The Netherlands.

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-β1 and whether expression of the genes PDGF-B and TGF-B1 (growth factors suggested to play a role in GO) are increased in GO orbital tissues.

METHODS. PDGF-B and TGF-B1 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-β1–induced orbital fibroblast proliferation, signaling cascades, hyaluronan synthase (HAS) gene expression and hyaluronan production were determined.

RESULTS. PDGF-B and TGF-B1 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-β1 induced HAS expression and hyaluronan production. This induction was not inhibited by imatinib mesylate or AMN107, due to the inability of TGF-β1 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-β1–induced HAS expression and hyaluronan production. Nevertheless, imatinib mesylate and AMN107 should be considered as treatment candidates for GO.




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