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.
authors.affiliation: Mammalian Genetics Unit (L.B., C.T.E., R.A.H., S.D.M.B., R.D.C.) and Mary Lyon Centre (C.L.S., T.A.H.), Medical Research Council Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, United Kingdom; Academic Endocrine Unit (C.T.E., M.A.N., R.A.H., F.M.H., R.V.T.), Nuffield Department of Clinical Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford OX3 7LE, United Kingdom; The Mellanby Centre for Bone Research (H.E., D.L.), Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom; Wellcome Trust Sanger Institute (C.P.), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; Norwich Medical School (W.D.F.), University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom; Garvan Institute of Medical Research (P.I.C.), Musculoskeletal Medicine Division, University of New South Wales, Sydney 2010, Australia; and University of Queensland Diamantina Institute (M.A.B.), Princess Alexandra Hospital, University of Queensland, Brisbane 4102, Australia.
authors.forename: Liz
authors.initials: L
authors.lastname: Bentley
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Esapa
authors.forename: M Andrew
authors.initials: MA
authors.lastname: Nesbit
authors.forename: Rosie A
authors.initials: RA
authors.lastname: Head
authors.forename: Holly
authors.initials: H
authors.lastname: Evans
authors.forename: Darren
authors.initials: D
authors.lastname: Lath
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.forename: Tertius A
authors.initials: TA
authors.lastname: Hough
authors.forename: Christine
authors.initials: C
authors.lastname: Podrini
authors.forename: Fadil M
authors.initials: FM
authors.lastname: Hannan
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.forename: Peter I
authors.initials: PI
authors.lastname: Croucher
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cox
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000818:Animals; D001823:Body Composition; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002874:Chromosome Mapping; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D003480:Cushing Syndrome / Q000235:genetics; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000737:chemistry*; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D005938:Glucocorticoids; D003346:Corticotropin-Releasing Hormone; D005038:Ethylnitrosourea; D002118:Calcium; D003345:Corticosterone