An N-ethyl-n-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess

Bentley, Liz, Esapa, Christopher T., Nesbit, M. Andrew, Head, Rosie A., Evans, Holly, Lath, Darren, Scudamore, Cheryl L., Hough, Tertius A., Podrini, Christine, Hannan, Fadil M., Fraser, William D., Croucher, Peter I., Brown, Matthew A., Brown, Steve D. M., Cox, Roger D. and Thakker, Rajesh V. (2014) An N-ethyl-n-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess. Endocrinology, 155 3: 908-922. doi:10.1210/en.2013-1247


Author Bentley, Liz
Esapa, Christopher T.
Nesbit, M. Andrew
Head, Rosie A.
Evans, Holly
Lath, Darren
Scudamore, Cheryl L.
Hough, Tertius A.
Podrini, Christine
Hannan, Fadil M.
Fraser, William D.
Croucher, Peter I.
Brown, Matthew A.
Brown, Steve D. M.
Cox, Roger D.
Thakker, Rajesh V.
Title An N-ethyl-n-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess
Journal name Endocrinology   Check publisher's open access policy
ISSN 0013-7227
1945-7170
Publication date 2014
Year available 2013
Sub-type Article (original research)
DOI 10.1210/en.2013-1247
Open Access Status DOI
Volume 155
Issue 3
Start page 908
End page 922
Total pages 15
Place of publication Chevy Chase, MD, United States
Publisher The Endocrine Society
Collection year 2014
Language eng
Abstract Cushing's syndrome, which is characterized by excessive circulating glucocorticoid concentrations, maybe 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. Copyright
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published Online: 3 December 2013.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
UQ Diamantina Institute Publications
 
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