Görtz Gina-Eva, Moshkelgosha Sajad, Jesenek Christoph, Edelmann Bärbel, Horstmann Mareike, Banga J Paul, Eckstein Anja, Berchner-Pfannschmidt Utta
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.
Endocrinology. 2016 Oct;157(10):3771-3778. doi: 10.1210/en.2016-1304. Epub 2016 Aug 23.
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.
最近建立了一种通过基因免疫编码人促甲状腺激素受体（TSHR）A亚基的质粒诱导的格雷夫斯眼眶病（GO）小鼠模型。眼眶病理特征为脂肪生成、肌病和纤维化。人眼眶成纤维细胞（OFs）表达TSHR和胰岛素样生长因子-1受体（IGF-1R），被认为在GO中具有致病性。我们建立了从患有GO的动物和对照的眼眶组织中培养小鼠OFs（mOFs）体外培养物的条件。早期传代的mOFs表现出典型的成纤维细胞形态，并表达间充质干细胞标志物，包括CD90.2和CD40的强表达，而CD73和所有其他白细胞标志物均未表达。重要的是，与对照相比，源自GO小鼠的OFs表达升高水平的TSHR和IGF-1R，并表现出增强的脂肪生成。用促甲状腺激素、单克隆促甲状腺抗体M22激活GO动物的mOFs中的TSHR，或用IGF-1刺激IGF-1R，与对照动物相比，可诱导透明质酸分泌显著升高。透明质酸合酶2在源自GO小鼠的OFs中更为丰富。总之，从GO模型建立的mOFs通过其增加的脂肪生成和透明质酸产生倾向导致疾病活动，概括了GO患者人OFs的致病性。据我们所知，这是第一份报告表明临床前GO模型的mOFs具有致病特性，这将有助于理解脂肪生成和透明质酸沉积过程中的分子和遗传变化，为GO发病机制提供新的见解。
