Platelet-Derived Growth Factor-BB Enhances Adipogenesis in Orbital Fibroblasts

Prayer Virakul, V.A.S.H. Dalm, D Paridaens, WA van den Bosch, Monique Mulder, N Hirankarn, P.M. van Hagen, Wim Dik

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Abstract

PURPOSE. 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)-gamma 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-c 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-a 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-gamma 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.
Original languageUndefined/Unknown
Pages (from-to)5457-5464
Number of pages8
JournalInvestigative Ophthalmology & Visual Science
Volume56
Issue number9
DOIs
Publication statusPublished - 2015

Research programs

  • EMC COEUR-09
  • EMC COEUR-09-39-01
  • EMC MM-02-72-02

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