Imatinib Mesylate and AMN107 Inhibit PDGF-Signaling in Orbital Fibroblasts: A Potential Treatment for Graves’ Ophthalmopathy

Abstract

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.

Transformujący czynnik wzrostu β1 (TGFβ1) i naczyniowo-śródbłonkowy czynnik wzrostu (VEGF) we krwi ludzi zdrowych i chorych z orbitopatią Gravesa — nowy mechanizm działania glikokortykosteroidów?

“…Stimulation of glycosaminoglycans production by the cytokine, released from lymphocytes or macrophages infiltrating the retroocular space, may play a role in the accumulation of glycosaminoglycans in the retroocular and perimysial connective tissues in GO [47,51]. TGFb increases hyaluronan (the major ECM glycosaminoglycan) secretion into the culture medium of orbital fibroblasts in vitro [40,42,51]. TGFb1 is one of the key mediators of fibrogenesis.…”

“…TGFb1 inhibits TSHR expression and adipogenesis by orbital fibroblasts in vitro, effects that would seem to favour disease remission [34,39]. TGFb mRNA levels have also been found to be present at higher levels in orbital tissue from GO patients compared to controls [40]. VEGF is produced by thyroid follicles in response to chronic activation of TSHR.…”

Mast Cell-derived Prostaglandin D2 Controls Hyaluronan Synthesis in Human Orbital Fibroblasts via DP1 Activation

“…Current evidence, including data from our laboratories (3,47,48), suggests that activation of orbital fibroblasts by infiltrating inflammatory cells, particularly T cells and mast cells, plays an important role in TED pathogenesis (49). Orbital fibroblast proliferation and ECM production, particularly HA (50,51), are key events that contribute to manifestations of TED, such as periorbital edema, exophthalmos, and extraocular motility dysfunction (1,52). Here, we have provided data indicating that mast cell-derived PGD 2 is a key factor that regulates the production of HA by orbital fibroblasts via activation of DP1 (Figs.…”

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Transforming Growth Factor-β-induced, Hyaluronan-dependent, T Cell Adhesion to Orbital Fibroblasts

“…Increased transforming growth factor ␤ (TGF-␤) mRNA levels have been observed in orbital tissue from patients with TED (29). TGF-␤ is a key cytokine that regulates ECM production, inflammation, fibrosis, and tissue remodeling.…”