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

doi:10.1167/iovs.15-17001

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

Orbita and oculoplastic surgery

Research output: Contribution to journal › Article › Research › peer-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 language	English
Pages (from-to)	5457-64
Number of pages	8
Journal	Investigative ophthalmology & visual science
Volume	56
Issue number	9
DOIs	https://doi.org/10.1167/iovs.15-17001
Publication status	Published - 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

Access to Document

10.1167/iovs.15-17001

Cite this

@article{0f513822275a4fb09764c31612e07f16,

title = "Platelet-Derived Growth Factor-BB Enhances Adipogenesis in Orbital Fibroblasts",

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.",

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",

author = "Sita Virakul and Dalm, {Virgil A S H} and Dion Paridaens and {van den Bosch}, {Willem A} and Mulder, {Monique T} and Nattiya Hirankarn and {van Hagen}, {P Martin} and Dik, {Willem A}",

year = "2015",

month = aug,

doi = "10.1167/iovs.15-17001",

language = "English",

volume = "56",

pages = "5457--64",

number = "9",

}

TY - JOUR

T1 - Platelet-Derived Growth Factor-BB Enhances Adipogenesis in Orbital Fibroblasts

AU - Virakul, Sita

AU - Dalm, Virgil A S H

AU - Paridaens, Dion

AU - van den Bosch, Willem A

AU - Mulder, Monique T

AU - Hirankarn, Nattiya

AU - van Hagen, P Martin

AU - Dik, Willem A

PY - 2015/8

Y1 - 2015/8

N2 - 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.

AB - 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.

KW - Adipogenesis

KW - Becaplermin

KW - Cells, Cultured

KW - Fibroblasts/metabolism

KW - Gene Expression Regulation

KW - Graves Ophthalmopathy/genetics

KW - Humans

KW - Orbit

KW - Proto-Oncogene Proteins c-sis/biosynthesis

KW - RNA, Messenger/genetics

KW - Real-Time Polymerase Chain Reaction

U2 - 10.1167/iovs.15-17001

DO - 10.1167/iovs.15-17001

M3 - Article

C2 - 26284551

SN - 0146-0404

VL - 56

SP - 5457

EP - 5464

JO - Investigative ophthalmology & visual science

JF - Investigative ophthalmology & visual science

IS - 9

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this