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.