An N-ethyl-N-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess.
An N-ethyl-N-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess.
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DOI：
10.1210/en.2013-1247
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发表时间：
2014-03
期刊：
影响因子：
4.8
通讯作者：
Thakker RV
中科院分区：
文献类型：
--
作者：
Bentley L;Esapa CT;Nesbit MA;Head RA;Evans H;Lath D;Scudamore CL;Hough TA;Podrini C;Hannan FM;Fraser WD;Croucher PI;Brown MA;Brown SD;Cox RD;Thakker RV
库欣综合征的特征是循环中糖皮质激素浓度过高，可能是由于ACTH依赖性或非依赖性的原因，分别包括垂体前叶和肾上腺皮质肿瘤。促肾上腺皮质激素分泌受CRH刺激，我们报告了一个库欣综合征的小鼠模型，该模型由N-乙基-N-亚硝基脲（ENU）诱导的启动子区-120 bp处的Crh突变引起，该突变显著增加了荧光素酶报告基因活性，因此是一种功能获得性突变。与野生型同窝小鼠相比，Crh-120/+小鼠出现肥胖、肌肉萎缩、皮肤变薄、脱发以及血浆和尿液中皮质酮浓度升高。此外，Crh−120/+小鼠有高血糖症、高果糖胺血症、高胰岛素血症、高胆固醇血症、高甘油三酯血症和高瘦素血症，但脂联素正常。Crh−120/+小鼠还具有低骨矿物质密度、高钙血症、高钙尿症以及血浆PTH和骨钙素浓度降低。骨组织形态计量学显示，Crh−120/+小鼠的矿化表面积、矿物质沉积、骨形成率、成骨细胞数量和成骨细胞覆盖的皮质骨内膜骨百分比显著降低，同时骨髓中脂肪细胞增加。因此，库欣氏综合征的小鼠模型已经建立，这将有助于进一步阐明糖皮质激素过量的病理生理学效应，并在评估治疗皮质类固醇诱导的骨质疏松症。
Cushing's syndrome, which is characterized by excessive circulating glucocorticoid concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumors, respectively. ACTH secretion is stimulated by CRH, and we report a mouse model for Cushing's syndrome due to an N-ethyl-N-nitrosourea (ENU) induced Crh mutation at −120 bp of the promoter region, which significantly increased luciferase reporter activity and was thus a gain-of-function mutation. Crh−120/+ mice, when compared with wild-type littermates, had obesity, muscle wasting, thin skin, hair loss, and elevated plasma and urinary concentrations of corticosterone. In addition, Crh−120/+ mice had hyperglycemia, hyperfructosaminemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and hyperleptinemia but normal adiponectin. Crh−120/+ mice also had low bone mineral density, hypercalcemia, hypercalciuria, and decreased concentrations of plasma PTH and osteocalcin. Bone histomorphometry revealed Crh−120/+ mice to have significant reductions in mineralizing surface area, mineral apposition, bone formation rates, osteoblast number, and the percentage of corticoendosteal bone covered by osteoblasts, which was accompanied by an increase in adipocytes in the bone marrow. Thus, a mouse model for Cushing's syndrome has been established, and this will help in further elucidating the pathophysiological effects of glucocorticoid excess and in evaluating treatments for corticosteroid-induced osteoporosis.
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影响因子：
4.1
作者：
Hattangady, Namita G.;Olala, Lawrence O.;Bollag, Wendy B.;Rainey, William E.
通讯作者：
Rainey, William E.
影响因子：
2.5
作者：
Hough, TA;Nolan, PM;Hunter, AJ
通讯作者：
Hunter, AJ
影响因子：
7.6
作者：
Budziszewska, B;Jaworska-Feil, L;Lason, W
通讯作者：
Lason, W
影响因子：
8.3
作者：
Bailey, Matthew A.;Mullins, John J.;Kenyon, Christopher J.
通讯作者：
Kenyon, Christopher J.
影响因子：
8.2
作者：
Carroll, Ty B.;Findling, James W.
通讯作者：
Findling, James W.