The Platelet-Derived Growth Factor Pathway: A Therapeutic Target in Graves' Ophthalmopathy?

Abstract

Purpose: : Excessive orbital fibroblast proliferation and hyaluronan production are key processes in the pathophysiology of Graves’ Ophthalmopathy (GO) that are driven by mediators present within the orbit. Imatinib mesylate and AMN107 are tyrosine kinase inhibitors that inhibit fibroblast proliferation and collagen production in the lungs and skin. This study was conducted to determine a) whether expression of the PDGF-B and TGF- β₁ genes was indeed increased in GO orbital tissues and b) whether imatinib mesylate and AMN107 inhibited orbital fibroblast proliferation and hyaluronan production induced by PDGF-BB and TGF-β₁ (growth factors suggested to play a role in GO).

Methods: : PDGF-B and TGF-β₁ mRNA levels were determined by real-time quantitative (RQ)-PCR in orbital tissues from thirteen GO patients and five controls. Orbital fibroblasts were cultured from eight GO patients and three controls and the effects of imatinib mesylate and AMN107 on PDGF-BB and TGF-β₁-induced orbital fibroblast proliferation, hyaluronan synthase (HAS) gene expression and hyaluronan production was determined using proliferation assays, RQ-PCR and ELISA.

Results: : PDGF-B and TGF-β₁ mRNA levels were significantly increased in GO orbital tissues. Imatinib mesylate and AMN107 efficiently inhibited PDGF-BB-induced orbital fibroblast proliferation, HAS induction and hyaluronan production. In addition, imatinib mesylate and AMN107 reduced hyaluronan production by orbital fibroblasts induced by co-stimulation with PDGF-BB and TGF-β₁.

Conclusions: : Imatinib mesylate and AMN107 inhibit orbital fibroblast proliferation and hyaluronan production induced by PDGF-BB; a factor highly expressed in orbital tissue from GO patients. Therefore, imatinib mesylate and AMN107 should be considered as treatment candidates for GO.

Keywords: growth factors/growth factor receptors • inflammation • orbit