Platelet-Derived Growth Factor-BB Enhances Adipogenesis in Orbital Fibroblasts.
OBJECTIVE
Platelet-derived growth factor (PDGF)-BB has been identified as important factor in pathogenesis of Graves' ophthalmopathy (GO). It stimulates proliferation, cytokine, and hyaluronan production, and thyrotropin receptor expression by orbital fibroblasts. Therefore, the PDGF-pathway has been proposed as a target for pharmacological intervention in GO. However, increased adipogenesis is another major pathological characteristic of GO and it is unknown whether this is affected by PDGF-BB. The aim of this study was to investigate the effect of PDGF-BB on adipocyte differentiation by orbital fibroblasts.


METHODS
Orbital fibroblasts from five healthy controls and nine GO patients were collected. Adipogenesis was induced by culturing orbital fibroblasts in differentiation medium, either in the presence or absence of PDGF-BB. Adipogenesis was determined by Oil-Red-O staining, triglyceride measurement, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA expression.


RESULTS
Platelet-derived growth factor-BB significantly enhanced adipocyte differentiation by orbital fibroblasts (Oil-Red-O staining [P < 0.0001], triglyceride measurement [P < 0.05], and PPAR-γ mRNA expression [P < 0.05]). It enhanced IL-6 production early during differentiation, but the effect of PDGF-BB on adipogenesis was independent of autocrine IL-6 signaling as it was not abrogated by IL-6-receptor-α neutralizing antibody. The clinically applicable tyrosine kinase inhibitor dasatinib and tyrphostin AG1296, which both block PDGF receptor tyrosine kinase activity, inhibited PDGF-BB-enhanced adipogenesis (P < 0.05) in orbital fibroblasts. Moreover, dasatinib reduced PPAR-γ mRNA expression in cultured GO orbital tissue.


CONCLUSIONS
Platelet-derived growth factor-BB enhances adipogenesis in orbital fibroblasts, and, thus, may contribute to adipose tissue expansion in GO. Therefore, the PDGF-signaling cascade may represent a target of therapy to interfere with adipogenesis in GO.
Department of Immunology Laboratory of Medical Immunology, Erasmus MC, Rotterdam, The Netherlands 2Internal Medicine, Division of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.
Sita
S
Virakul
Department of Immunology Laboratory of Medical Immunology, Erasmus MC, Rotterdam, The Netherlands 2Internal Medicine, Division of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.
Virgil A S H
VA
Dalm
Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Dion
D
Paridaens
Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Willem A
WA
van den Bosch
Internal Medicine, Division of Pharmacology, Vascular and Metabolic Diseases, Erasmus MC, Rotterdam, The Netherlands.
Monique T
MT
Mulder
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 of Medical Immunology, Erasmus MC, Rotterdam, The Netherlands 2Internal Medicine, Division of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands 3Rotterdam Eye Hospital, Rotterdam, The Netherlands.
P Martin
PM
van Hagen
Department of Immunology Laboratory of Medical Immunology, Erasmus MC, Rotterdam, The Netherlands.
Willem A
WA
Dik
D050156:Adipogenesis; D000077214:Becaplermin; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D049970:Graves Ophthalmopathy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009915:Orbit; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D000077214:Becaplermin