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

Sita Virakul, Virgil A S H Dalm, Dion Paridaens, Willem A van den Bosch, Monique T Mulder, Nattiya Hirankarn, P Martin van Hagen, Willem A Dik

Research output: Contribution to journalArticleResearchpeer-review

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)-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.

Original languageEnglish
Pages (from-to)5457-64
Number of pages8
JournalInvestigative ophthalmology & visual science
Volume56
Issue number9
DOIs
Publication statusPublished - Aug 2015

Keywords

  • Adipogenesis
  • Becaplermin
  • Cells, Cultured
  • Fibroblasts/metabolism
  • Gene Expression Regulation
  • Graves Ophthalmopathy/genetics
  • Humans
  • Orbit
  • Proto-Oncogene Proteins c-sis/biosynthesis
  • RNA, Messenger/genetics
  • Real-Time Polymerase Chain Reaction

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