title: Pathogenic Phenotype of Adipogenesis and Hyaluronan in Orbital Fibroblasts From Female Graves' Orbitopathy Mouse Model.
abstract: A mouse model of Graves' orbitopathy (GO) induced by genetic immunization of human TSH receptor (TSHR) A-subunit encoding plasmid has recently been established. The orbital pathology was characterized by adipogenesis, myopathy and fibrosis. Human orbital fibroblasts (OFs) express TSHR and IGF-1 receptor (IGF-1R) and are considered to be pathogenic in GO. We established conditions for growing ex vivo cultures of mouse OFs (mOFs) from orbital tissue of animals undergoing GO and controls. Early passage mOFs showed characteristic fibroblast morphology and expressed mesenchymal stem cell markers including a strong expression of CD90.2 and CD40, whereas display of CD73 and all other leucocyte markers was uniformly absent. Importantly, OFs derived from GO mice expressed elevated levels of TSHR and IGF-1R and showed enhanced adipogensis compared with controls. Activation of TSHR in mOFs from GO animals with TSH, monoclonal thyroid-stimulating antibody M22, or stimulation of IGF-1R with IGF-1-induced hyaluronan secretion to significantly elevated levels compared with control animals. Hyaluronan synthase 2 was more abundant in OFs derived from GO mice. In conclusion, mOFs established from GO model recapitulate the pathogenicity of human OFs from GO patients by their increased propensity for adipogenesis and hyaluronan production leading to disease activity. To our knowledge, this is the first report to show mOFs from the preclinical GO model have pathogenic properties that will aid in understanding the molecular and genetic changes during progression to adipogenesis and hyaluronan deposition to provide new insights into GO pathogenesis.
authors.affiliation: Molecular Ophthalmology (G.-E.G., S.M., C.J., M.H., J.P.B., A.E., U.B.-P.), Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; and Department for Hematology and Oncology (B.E.), Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Gina-Eva
authors.initials: GE
authors.lastname: Görtz
authors.affiliation: Molecular Ophthalmology (G.-E.G., S.M., C.J., M.H., J.P.B., A.E., U.B.-P.), Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; and Department for Hematology and Oncology (B.E.), Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Sajad
authors.initials: S
authors.lastname: Moshkelgosha
authors.affiliation: Molecular Ophthalmology (G.-E.G., S.M., C.J., M.H., J.P.B., A.E., U.B.-P.), Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; and Department for Hematology and Oncology (B.E.), Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Jesenek
authors.affiliation: Molecular Ophthalmology (G.-E.G., S.M., C.J., M.H., J.P.B., A.E., U.B.-P.), Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; and Department for Hematology and Oncology (B.E.), Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Edelmann
authors.affiliation: Molecular Ophthalmology (G.-E.G., S.M., C.J., M.H., J.P.B., A.E., U.B.-P.), Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; and Department for Hematology and Oncology (B.E.), Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Horstmann
authors.affiliation: Molecular Ophthalmology (G.-E.G., S.M., C.J., M.H., J.P.B., A.E., U.B.-P.), Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; and Department for Hematology and Oncology (B.E.), Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Banga
authors.affiliation: Molecular Ophthalmology (G.-E.G., S.M., C.J., M.H., J.P.B., A.E., U.B.-P.), Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; and Department for Hematology and Oncology (B.E.), Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Eckstein
authors.affiliation: Molecular Ophthalmology (G.-E.G., S.M., C.J., M.H., J.P.B., A.E., U.B.-P.), Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; and Department for Hematology and Oncology (B.E.), Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Utta
authors.initials: U
authors.lastname: Berchner-Pfannschmidt
mesh_terms: D050156:Adipogenesis; D000818:Animals; D004195:Disease Models, Animal; D005123:Eye / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D049970:Graves Ophthalmopathy / Q000378:metabolism / Q000473:pathology*; D006820:Hyaluronic Acid / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I; D008807:Mice, Inbred BALB C; D010641:Phenotype; D013972:Thyrotropin
chemical_list: D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D006820:Hyaluronic Acid