Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves' ophthalmopathy

Leendert van Steensel; Dion Paridaens; Benjamin Schrijver; Gemma M Dingjan; Paul L A van Daele; P Martin van Hagen; Willem A van den Bosch; Hemmo A Drexhage; Herbert Hooijkaas; Willem A Dik

doi:10.1167/iovs.08-2443

Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves' ophthalmopathy

Leendert van Steensel, Dion Paridaens, Benjamin Schrijver, Gemma M Dingjan, Paul L A van Daele, P Martin van Hagen, Willem A van den Bosch, Hemmo A Drexhage, Herbert Hooijkaas, Willem A Dik

Orbita and oculoplastic surgery

Research output: Contribution to journal › Article › Research › peer-review

Abstract

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.

Original language	English
Pages (from-to)	3091-8
Number of pages	8
Journal	Investigative ophthalmology & visual science
Volume	50
Issue number	7
DOIs	https://doi.org/10.1167/iovs.08-2443
Publication status	Published - Jul 2009

Keywords

Adult
Aged
Aged, 80 and over
Becaplermin
Benzamides
Cell Proliferation/drug effects
Cells, Cultured
Female
Fibroblasts/metabolism
Gene Expression Regulation/physiology
Glucuronosyltransferase/genetics
Graves Ophthalmopathy/drug therapy
Humans
Hyaluronan Synthases
Hyaluronic Acid/biosynthesis
Imatinib Mesylate
Male
Middle Aged
Orbit/metabolism
Phosphorylation
Piperazines/pharmacology
Platelet-Derived Growth Factor/antagonists & inhibitors
Polymerase Chain Reaction
Protein Kinase Inhibitors/pharmacology
Protein-Tyrosine Kinases/antagonists & inhibitors
Proto-Oncogene Proteins c-abl/metabolism
Proto-Oncogene Proteins c-sis/genetics
Pyrimidines/pharmacology
RNA, Messenger/metabolism
Receptors, Platelet-Derived Growth Factor/metabolism
Signal Transduction/drug effects
Transforming Growth Factor beta1/genetics

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10.1167/iovs.08-2443

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van Steensel, L., Paridaens, D., Schrijver, B., Dingjan, G. M., van Daele, P. L. A., van Hagen, P. M., van den Bosch, W. A., Drexhage, H. A., Hooijkaas, H., & Dik, W. A. (2009). Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves' ophthalmopathy. Investigative ophthalmology & visual science, 50(7), 3091-8. https://doi.org/10.1167/iovs.08-2443

@article{d2be2aa675d34f3e8ef1ec0a6b465e7a,

title = "Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves' ophthalmopathy",

abstract = "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.",

keywords = "Adult, Aged, Aged, 80 and over, Becaplermin, Benzamides, Cell Proliferation/drug effects, Cells, Cultured, Female, Fibroblasts/metabolism, Gene Expression Regulation/physiology, Glucuronosyltransferase/genetics, Graves Ophthalmopathy/drug therapy, Humans, Hyaluronan Synthases, Hyaluronic Acid/biosynthesis, Imatinib Mesylate, Male, Middle Aged, Orbit/metabolism, Phosphorylation, Piperazines/pharmacology, Platelet-Derived Growth Factor/antagonists & inhibitors, Polymerase Chain Reaction, Protein Kinase Inhibitors/pharmacology, Protein-Tyrosine Kinases/antagonists & inhibitors, Proto-Oncogene Proteins c-abl/metabolism, Proto-Oncogene Proteins c-sis/genetics, Pyrimidines/pharmacology, RNA, Messenger/metabolism, Receptors, Platelet-Derived Growth Factor/metabolism, Signal Transduction/drug effects, Transforming Growth Factor beta1/genetics",

author = "{van Steensel}, Leendert and Dion Paridaens and Benjamin Schrijver and Dingjan, {Gemma M} and {van Daele}, {Paul L A} and {van Hagen}, {P Martin} and {van den Bosch}, {Willem A} and Drexhage, {Hemmo A} and Herbert Hooijkaas and Dik, {Willem A}",

year = "2009",

month = jul,

doi = "10.1167/iovs.08-2443",

language = "English",

volume = "50",

pages = "3091--8",

number = "7",

}

van Steensel, L, Paridaens, D, Schrijver, B, Dingjan, GM, van Daele, PLA, van Hagen, PM, van den Bosch, WA, Drexhage, HA, Hooijkaas, H & Dik, WA 2009, 'Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves' ophthalmopathy', Investigative ophthalmology & visual science, vol. 50, no. 7, pp. 3091-8. https://doi.org/10.1167/iovs.08-2443

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

SN - 0146-0404

VL - 50

SP - 3091

EP - 3098

JO - Investigative ophthalmology & visual science

JF - Investigative ophthalmology & visual science

IS - 7

ER -

Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves' ophthalmopathy

Abstract

Keywords

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