nintedanib and Graves-Ophthalmopathy

Basic fibroblast growth factor (bFGF) has been implicated in the pathogenesis of Graves' orbitopathy (GO). It stimulates several processes, including hyaluronan synthesis, involved in orbital tissue volume expansion and may act synergistically with platelet-derived growth factor (PDGF)-BB. PDGF-BB is known to stimulate adipogenesis in orbital fibroblasts, but the effect of bFGF on adipogenesis in orbital fibroblasts is so far unknown. This study was conducted to determine whether (i) bFGF induces adipogenesis in orbital fibroblasts, (ii) bFGF and PDGF-BB together exert an additive or synergistic effect on adipogenesis, and (iii) treatment directed at bFGF- and PDGF-BB signaling may potentially be of interest for the treatment of GO.. Orbital fibroblasts from GO patients and controls were cultured in adipocyte differentiation medium with or without bFGF and/or PDGF-BB at different concentrations. Adipogenesis was determined by Oil Red O staining and messenger RNA expression of the late adipocyte differentiation markers cell death-inducing DFFA-like effector C (CIDEC) and adiponectin (ADIPOQ). To demonstrate involvement of FGF-receptor and PDGF-receptor signaling, experiments were also conducted in the presence of dasatinib (inhibitor of PDGF-receptor) or nintedanib (inhibitor of PDGF-receptor and FGF-receptor).. bFGF significantly stimulated adipogenesis by orbital fibroblasts, as shown by increased Oil Red O staining and CIDEC and ADIPOQ expression after 14 days of differentiation. Furthermore, an additive effect of bFGF/PDGF-BB co-stimulation on adipogenesis was observed at the lowest concentration (12.5 ng/mL) of the growth factors tested. Nintedanib completely inhibited bFGF-, PDGF-BB-, and bFGF/PDGF-BB-induced adipogenesis, while dasatinib only fully abrogated PDGF-BB-induced adipogenesis.. bFGF induces adipogenesis in orbital fibroblasts and as such may contribute to GO. The additive effect of bFGF and PDGF-BB on adipogenesis, along with the observed inhibitory effects of dasatinib and nintedanib, point at independent receptor-mediated effects. This supports the hypothesis that multi-target directed therapy might be more efficient in the treatment of GO.

Topics: Adipocytes; Adipogenesis; Azo Compounds; Becaplermin; Cell Differentiation; Dasatinib; Fibroblast Growth Factor 2; Fibroblasts; Graves Ophthalmopathy; Humans; Indoles; Lipids; Orbit; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Signal Transduction

Orbital fibroblast activation is a central pathologic feature of Graves' Ophthalmopathy (GO). Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been proposed to contribute to GO, but their effects on orbital fibroblasts are largely unknown. We found that bFGF stimulated proliferation and hyaluronan production, but not IL-6 production by orbital fibroblasts, while VEGF hardly affected orbital fibroblast activity. Remarkably, co-stimulation of orbital fibroblasts with bFGF and PDGF-BB synergistically enhanced IL-6 and hyaluronan production and displayed an additive effect on proliferation compared to either bFGF or PDGF-BB stimulation. Nintedanib, a FGF- and PDGF-receptor targeting drug, more efficiently blocked bFGF + PDGF-BB-induced IL-6 and hyaluronan production than dasatinib that only targets PDGF-receptor. In conclusion, bFGF may contribute to orbital inflammation and tissue remodeling in GO, especially through synergistic interaction with PDGF-BB. Multi-target therapy directed at the bFGF and PDGF pathways may potentially be of interest for the treatment of GO.

Topics: Adult; Becaplermin; Cell Proliferation; Cells, Cultured; Dasatinib; Female; Fibroblast Growth Factors; Fibroblasts; Graves Ophthalmopathy; Humans; Hyaluronic Acid; Indoles; Interleukin-6; Male; Middle Aged; Proto-Oncogene Proteins c-sis; Receptors, Platelet-Derived Growth Factor; Vascular Endothelial Growth Factor A