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)-c 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-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.

Adipogenesis, Graves’ ophthalmopathy, Orbital fibroblast, Platelet-derived growth factor-BB
dx.doi.org/10.1167/iovs.15-17001, hdl.handle.net/1765/82892
Investigative Ophthalmology & Visual Science
Department of Internal Medicine

Virakul, S, Dalm, V.A.S.H, Paridaens, A.D.A, van den Bosch, W.A, Mulder, M.T, Hirankarn, N, … Dik, W.A. (2015). Platelet-derived growth factor-BB enhances adipogenesis in orbital fibroblasts. Investigative Ophthalmology & Visual Science, 56(9), 5457–5464. doi:10.1167/iovs.15-17001