Sita Virakul1, Virgil A S H Dalm1, Dion Paridaens2, Willem A van den Bosch2, Monique T Mulder3, Nattiya Hirankarn4, P Martin van Hagen5, Willem A Dik6. 1. Department of Immunology Laboratory of Medical Immunology, Erasmus MC, Rotterdam, The Netherlands 2Internal Medicine, Division of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands. 2. Rotterdam Eye Hospital, Rotterdam, The Netherlands. 3. Internal Medicine, Division of Pharmacology, Vascular and Metabolic Diseases, Erasmus MC, Rotterdam, The Netherlands. 4. Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 5. 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. 6. Department of Immunology Laboratory of Medical Immunology, Erasmus MC, Rotterdam, The Netherlands.
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.
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 tyrphostinAG1296, 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.
Authors: Elizabeth Brett; Natalie Chung; William Tripp Leavitt; Arash Momeni; Michael T Longaker; Derrick C Wan Journal: Tissue Eng Part B Rev Date: 2017-04-27 Impact factor: 6.389
Authors: Charles P Blackshear; John S Flacco; Stephanie M Vistnes; Natalie N Chung; Dre Irizarry; Elizabeth A Brett; Derek J Yen; Arash Momeni; Michael T Longaker; Derrick C Wan Journal: Ann Plast Surg Date: 2017-12 Impact factor: 1.539
Authors: Sita Virakul; Poorichaya Somparn; Trairak Pisitkun; Peter J van der Spek; Virgil A S H Dalm; Dion Paridaens; P Martin van Hagen; Nattiya Hirankarn; Tanapat Palaga; Willem A Dik Journal: Front Endocrinol (Lausanne) Date: 2021-02-15 Impact factor: 5.555