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

Liz Bentley, Christopher T Esapa, M. Andrew Nesbit, Rosie A Head, Holly Evans, Darren Lath, Cheryl L Scudamore, Tertius A Hough, Christine Podrini, Fadil M Hannan, William D Fraser, Peter I Croucher, Matthew A Brown, Steve D M Brown, Roger D Cox, Rajesh V Thakker

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.
LanguageEnglish
Pages908-22
JournalEndocrinology
Volume155
Issue number3
Publication statusPublished - 2014

Fingerprint

Ethylnitrosourea
Corticotropin-Releasing Hormone
Glucocorticoids
Mutation
Cushing Syndrome
Osteoblasts
Adrenocorticotropic Hormone
Hypercalciuria
Bone and Bones
Hypertriglyceridemia
Adiponectin
Osteocalcin
Alopecia
Hyperinsulinism
Hypercalcemia
Corticosterone
Hypercholesterolemia
Luciferases
Adipocytes
Genetic Promoter Regions

Keywords

  • Cushing's syndrome
  • Mouse model
  • corticotropin-releasing hormone

Cite this

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. / An N-ethyl-N-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess. In: Endocrinology. 2014 ; Vol. 155, No. 3. pp. 908-22.
@article{fe42caf99cdf484187e5e6f708d6ce2d,
title = "An N-ethyl-N-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess.",
abstract = "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.",
keywords = "Cushing's syndrome, Mouse model, corticotropin-releasing hormone",
author = "Liz Bentley and Esapa, {Christopher T} and Nesbit, {M. Andrew} and Head, {Rosie A} and Holly Evans and Darren Lath and Scudamore, {Cheryl L} and Hough, {Tertius A} and Christine Podrini and Hannan, {Fadil M} and Fraser, {William D} and Croucher, {Peter I} and Brown, {Matthew A} and Brown, {Steve D M} and Cox, {Roger D} and Thakker, {Rajesh V}",
year = "2014",
language = "English",
volume = "155",
pages = "908--22",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "Endocrine Society",
number = "3",

}

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, SDM, Cox, RD & Thakker, RV 2014, 'An N-ethyl-N-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess.', Endocrinology, vol. 155, no. 3, pp. 908-22.

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; Thakker, Rajesh V.

In: Endocrinology, Vol. 155, No. 3, 2014, p. 908-22.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An N-ethyl-N-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess.

AU - Bentley, Liz

AU - Esapa, Christopher T

AU - Nesbit, M. Andrew

AU - Head, Rosie A

AU - Evans, Holly

AU - Lath, Darren

AU - Scudamore, Cheryl L

AU - Hough, Tertius A

AU - Podrini, Christine

AU - Hannan, Fadil M

AU - Fraser, William D

AU - Croucher, Peter I

AU - Brown, Matthew A

AU - Brown, Steve D M

AU - Cox, Roger D

AU - Thakker, Rajesh V

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Cushing's syndrome

KW - Mouse model

KW - corticotropin-releasing hormone

M3 - Article

VL - 155

SP - 908

EP - 922

JO - Endocrinology

T2 - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 3

ER -