Basic FGF and PDGF-BB synergistically stimulate hyaluronan and IL-6 production by orbital fibroblasts.
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.
Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, The Netherlands; Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.
Sita
S
Virakul
Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
Judith W
JW
Heutz
Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, The Netherlands; Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.
Virgil A S H
VA
Dalm
Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
Robin P
RP
Peeters
Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Dion
D
Paridaens
Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Willem A
WA
van den Bosch
Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Nattiya
N
Hirankarn
Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, The Netherlands; Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands; Rotterdam Eye Hospital, Rotterdam, The Netherlands.
P Martin
PM
van Hagen
Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, The Netherlands. Electronic address: w.dik@erasmusmc.nl.
Willem A
WA
Dik
D000328:Adult; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib / Q000494:pharmacology; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D049970:Graves Ophthalmopathy / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C508600:IL6 protein, human; D007211:Indoles; D015850:Interleukin-6; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin; D005346:Fibroblast Growth Factors; D006820:Hyaluronic Acid; D017479:Receptors, Platelet-Derived Growth Factor; C530716:nintedanib; D000069439:Dasatinib
Fibroblast growth factor; Graves’ ophthalmopathy; Hyaluronan; Orbital fibroblast; Platelet-derived growth factor-BB; Vascular endothelial growth factor