Glucocorticoid signaling in health and disease: Insights from tissue-Specific GR knockout mice

Endocrinology

Volumn 159, Issue 1, 2018, Pages 46-61

  Whirledge, Shannon ^a   DeFranco, Donald B ^b  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOCORTICOID; GLUCOCORTICOID RECEPTOR;

CARDIOVASCULAR DISEASE; CENTRAL NERVOUS SYSTEM DISEASE; GASTROINTESTINAL DISEASE; GENE TARGETING; GENETIC CODE; GENITAL SYSTEM DISEASE; IMMUNOPATHOLOGY; INTEGUMENTARY SYSTEM; KIDNEY DISEASE; KNOCKOUT MOUSE; LUNG DISEASE; METABOLISM; MOUSE; MUSCULOSKELETAL DISEASE; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; TISSUE SPECIFICITY; TRANSGENIC MOUSE; AGONISTS; ANIMAL; ANTIBODY SPECIFICITY; GENETICS; HUMAN;

ANIMALS; GLUCOCORTICOIDS; HUMANS; MICE, KNOCKOUT; ORGAN SPECIFICITY; RECEPTORS, GLUCOCORTICOID; SIGNAL TRANSDUCTION;

EID: 85040715921     PISSN: 00137227     EISSN: 19457170     Source Type: Journal    
DOI: 10.1210/en.2017-00728     Document Type: Review

References (136)

1. Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985;318(6047):635–641.
2. Kumar R, Thompson EB. Gene regulation by the glucocorticoid receptor: structure:function relationship. J Steroid Biochem Mol Biol. 2005;94(5):383–394.
3. Luisi BF, Xu WX, Otwinowski Z, Freedman LP, Yamamoto KR, Sigler PB. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature. 1991;352(6335): 497–505.
4. Surjit M, Ganti KP, Mukherji A, Ye T, Hua G, Metzger D, Li M, Chambon P. Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell. 2011;145(2):224–241.
5. Weikum ER, Knuesel MT, Ortlund EA, Yamamoto KR. Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol. 2017;18(3):159–174.
6. Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell. 2002;110(1):93–105.
7. Kirschke E, Goswami D, Southworth D, Griffin PR, Agard DA. Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles. Cell. 2014;157(7): 1685–1697.
8. Yang J, DeFranco DB. Assessment of glucocorticoid receptor-heat shock protein 90 interactions in vivo during nucleocytoplasmic trafficking. Mol Endocrinol. 1996;10(1):3–13.
9. Davies TH, Ning YM, Sánchez ER. A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J Biol Chem. 2002;277(7):4597–4600.
10. Echeverría PC, Mazaira G, Erlejman A, Gomez-Sanchez C, Piwien Pilipuk G, Galigniana MD. Nuclear import of the glucocorticoid receptor-hsp90 complex through the nuclear pore complex is mediated by its interaction with Nup62 and importin b. Mol Cell Biol. 2009;29(17):4788–4797.
11. Yamamoto KR, Darimont BD, Wagner RL, Iñiguez-Lluhí JA. Building transcriptional regulatory complexes: signals and surfaces. Cold Spring Harb Symp Quant Biol. 1998;63: 587–598.
12. Oakley RH, Ren R, Cruz-Topete D, Bird GS, Myers PH, Boyle MC, Schneider MD, Willis MS, Cidlowski JA. Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease. Proc Natl Acad Sci USA. 2013;110(42): 17035–17040.
13. Presman DM, Ball DA, Paakinaho V, Grimm JB, Lavis LD, Karpova TS, Hager GL. Quantifying transcription factor binding dynamics at the single-molecule level in live cells. Methods. 2017; 123:76–88.
14. Goldstein I, Baek S, Presman DM, Paakinaho V, Swinstead EE, Hager GL. Transcription factor assisted loading and enhancer dynamics dictate the hepatic fasting response. Genome Res. 2017; 27(3):427–439.
15. Oakley RH, Sar M, Cidlowski JA. The human glucocorticoid receptor b isoform. Expression, biochemical properties, and putative function. J Biol Chem. 1996;271(16):9550–9559.
16. Anbalagan M, Huderson B, Murphy L, Rowan BG. Post-translational modifications of nuclear receptors and human disease. Nucl Recept Signal. 2012;10:e001.
17. Wallace AD, Cidlowski JA. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J Biol Chem. 2001;276(46):42714–42721.
18. Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980; 284(5756):555–556.
19. Viegas LR, Hoijman E, Beato M, Pecci A. Mechanisms involved in tissue-specific apopotosis regulated by glucocorticoids. J Steroid Biochem Mol Biol. 2008;109(3-5):273–278.
20. Li Z, Dong J, Zou T, Du C, Li S, Chen C, Liu R, Wang K. Dexamethasone induces docetaxel and cisplatin resistance partially through up-regulating Krüppel-like factor 5 in triple-negative breast cancer. Oncotarget. 2017;8(7):11555–11565.
21. Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuro-immunomodulation. 2015;22(1-2):20–32.
22. Whirledge S, Cidlowski JA. Glucocorticoids and reproduction: traffic control on the road to reproduction. Trends Endocrinol Metab. 2017;28(6):399–415.
23. Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schütz G. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 1995;9(13):1608–1621.
24. Gesina E, Blondeau B, Milet A, Le Nin I, Duchene B, Czernichow P, Scharfmann R, Tronche F, Breant B. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects. Diabetologia. 2006;49(12):2939–2947.
25. Pepin MC, Pothier F, Barden N. Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature. 1992;355(6362):725–728.
26. Korte SM, De Kloet ER, Buwalda B, Bouman SD, Bohus B. Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test. Eur J Pharmacol. 1996;301(1-3):19–25.
27. Verma IM, Somia N. Gene therapy—promises, problems and prospects. Nature. 1997;389(6648):239–242.
28. Brewer JA, Khor B, Vogt SK, Muglia LM, Fujiwara H, Haegele KE, Sleckman BP, Muglia LJ. T-cell glucocorticoid receptor is required to suppress COX-2-mediated lethal immune activation. Nat Med. 2003;9(10):1318–1322.
29. Mittelstadt PR, Monteiro JP, Ashwell JD. Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness. J Clin Invest. 2012;122(7):2384–2394.
30. Jeanneteau FD, Lambert WM, Ismaili N, Bath KG, Lee FS, Garabedian MJ, Chao MV. BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus. Proc Natl Acad Sci USA. 2012;109(4):1305–1310.
31. Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, Bock R, Klein R, Schütz G. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet. 1999;23(1):99–103.
32. Tuckermann JP, Kleiman A, Moriggl R, Spanbroek R, Neumann A, Illing A, Clausen BE, Stride B, Förster I, Habenicht AJ, Reichardt HM, Tronche F, Schmid W, Schütz G. Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J Clin Invest. 2007;117(5):1381–1390.
33. Laryea G, Schütz G, Muglia LJ. Disrupting hypothalamic glucocorticoid receptors causes HPA axis hyperactivity and excess adiposity. Mol Endocrinol. 2013;27(10):1655–1665.
34. Kellendonk C, Eiden S, Kretz O, Schütz G, Schmidt I, Tronche F, Simon E. Inactivation of the GR in the nervous system affects energy accumulation. Endocrinology. 2002;143(6):2333–2340.
35. Boyle MP, Brewer JA, Funatsu M, Wozniak DF, Tsien JZ, Izumi Y, Muglia LJ. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proc Natl Acad Sci USA. 2005;102(2):473–478.
36. Boyle MP, Kolber BJ, Vogt SK, Wozniak DF, Muglia LJ. Forebrain glucocorticoid receptors modulate anxiety-associated locomotor activation and adrenal responsiveness. J Neurosci. 2006;26(7): 1971–1978.
37. Furay AR, Bruestle AE, Herman JP. The role of the forebrain glucocorticoid receptor in acute and chronic stress. Endocrinology. 2008;149(11):5482–5490.
38. Solomon MB, Furay AR, Jones K, Packard AE, Packard BA, Wulsin AC, Herman JP. Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females. Neuroscience. 2012;203:135–143.
39. Erdmann G, Schütz G, Berger S. Loss of glucocorticoid receptor function in the pituitary results in early postnatal lethality. Endocrinology. 2008;149(7):3446–3451.
40. Schmidt MV, Sterlemann V, Wagner K, Niederleitner B, Ganea K, Liebl C, Deussing JM, Berger S, Schütz G, Holsboer F, Müller MB. Postnatal glucocorticoid excess due to pituitary glucocorticoid receptor deficiency: differential short- and long-term consequences. Endocrinology. 2009;150(6):2709–2716.
41. Vincent MY, Hussain RJ, Zampi ME, Sheeran K, Solomon MB, Herman JP, Khan A, Jacobson L. Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors. Brain Res. 2013;1525:1–15.
42. Solomon MB, Loftspring M, de Kloet AD, Ghosal S, Jankord R, Flak JN, Wulsin AC, Krause EG, Zhang R, Rice T, McKlveen J, Myers B, Tasker JG, Herman JP. Neuroendocrine function after hypothalamic depletion of glucocorticoid receptors in male and female mice. Endocrinology. 2015;156(8):2843–2853.
43. Nahar J, Haam J, Chen C, Jiang Z, Glatzer NR, Muglia LJ, Dohanich GP, Herman JP, Tasker JG. Rapid nongenomic glucocorticoid actions in male mouse hypothalamic neuroendocrine cells are dependent on the nuclear glucocorticoid receptor. Endocrinology. 2015;156(8):2831–2842.
44. Shibata M, Banno R, Sugiyama M, Tominaga T, Onoue T, Tsunekawa T, Azuma Y, Hagiwara D, Lu W, Ito Y, Goto M, Suga H, Sugimura Y, Oiso Y, Arima H. AgRP neuron-specific deletion of glucocorticoid receptor leads to increased energy expenditure and decreased body weight in female mice on a high-fat diet. Endocrinology. 2016;157(4):1457–1466.
45. Ambroggi F, Turiault M, Milet A, Deroche-Gamonet V, Parnaudeau S, Balado E, Barik J, van der Veen R, Maroteaux G, Lemberger T, Schütz G, Lazar M, Marinelli M, Piazza PV, Tronche F. Stress and addiction: glucocorticoid receptor in dopaminoceptive neurons facilitates cocaine seeking. Nat Neurosci. 2009;12(3):247–249.
46. Barik J, Marti F, Morel C, Fernandez SP, Lanteri C, Godeheu G, Tassin JP, Mombereau C, Faure P, Tronche F. Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons. Science. 2013;339(6117):332–335.
47. Parnaudeau S, Dongelmans ML, Turiault M, Ambroggi F, Delbes AS, Cansell C, Luquet S, Piazza PV, Tronche F, Barik J. Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine. Front Behav Neurosci. 2014;8:35.
48. Parlato R, Otto C, Tuckermann J, Stotz S, Kaden S, Gröne HJ, Unsicker K, Schütz G. Conditional inactivation of glucocorticoid receptor gene in dopamine-b-hydroxylase cells impairs chromaffin cell survival. Endocrinology. 2009;150(4):1775–1781.
49. Chmielarz P, Ku´ smierczyk J, Parlato R, Schütz G, Nalepa I, Kreiner G. Inactivation of glucocorticoid receptor in noradrenergic system influences anxiety- and depressive-like behavior in mice. PLoS One. 2013;8(8):e72632.
50. Oakley RH, Cidlowski JA. Glucocorticoid signaling in the heart: a cardiomyocyte perspective. J Steroid Biochem Mol Biol. 2015; 153:27–34.
51. Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts AC, Leufkens HG, Walker BR. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart. 2004;90(8):859–865.
52. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36(4):385–486.
53. Cruz-Topete D, Myers PH, Foley JF, Willis MS, Cidlowski JA. Corticosteroids are essential for maintaining cardiovascular function in male mice. Endocrinology. 2016;157(7):2759–2771.
54. Addison T. On the Constitution and Local Effects of Disease of the Suprarenal Capsules. London, England: Samuel Highley; 1855.
55. Rog-Zielinska EA, Thomson A, Kenyon CJ, Brownstein DG, Moran CM, Szumska D, Michailidou Z, Richardson J, Owen E, Watt A, Morrison H, Forrester LM, Bhattacharya S, Holmes MC, Chapman KE. Glucocorticoid receptor is required for foetal heart maturation. Hum Mol Genet. 2013;22(16):3269–3282.
56. Richardson RV, Batchen EJ, Thomson AJ, Darroch R, Pan X, Rog-Zielinska EA, Wyrzykowska W, Scullion K, Al-Dujaili EA, Diaz ME, Moran CM, Kenyon CJ, Gray GA, Chapman KE. Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis. J Endocrinol. 2017;232(3):437–450.
57. Duma D, Collins JB, Chou JW, Cidlowski JA. Sexually dimorphic actions of glucocorticoids provide a link to inflammatory diseases with gender differences in prevalence. Sci Signal. 2010;3(143): ra74.
58. Goodwin JE, Zhang J, Geller DS. A critical role for vascular smooth muscle in acute glucocorticoid-induced hypertension. J Am Soc Nephrol. 2008;19(7):1291–1299.
59. Goodwin JE, Zhang J, Gonzalez D, Albinsson S, Geller DS. Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension. J Hypertens. 2011;29(7):1347–1356.
60. Goodwin JE, Feng Y, Velazquez H, Sessa WC. Endothelial glucocorticoid receptor is required for protection against sepsis. Proc Natl Acad Sci USA. 2013;110(1):306–311.
61. Agah R, Frenkel PA, French BA, Michael LH, Overbeek PA, Schneider MD. Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J Clin Invest. 1997;100(1):169–179.
62. Sainte-Marie Y, Nguyen Dinh Cat A, Perrier R, Mangin L, Soukaseum C, Peuchmaur M, Tronche F, Farman N, Escoubet B, Benitah JP, Jaisser F. Conditional glucocorticoid receptor expression in the heart induces atrio-ventricular block. FASEB J. 2007;21(12):3133–3141.
63. Gagnon S, Atmodjo W, Humes D, McKerlie C, Kaplan F, Sweezey NB. Transgenic glucocorticoid receptor expression driven by the SP-C promoter reduces neonatal lung cellularity and midkine expression in GRhypo mice. Biol Neonate. 2006;90(1):46–57.
64. Manwani N, Gagnon S, Post M, Joza S, Muglia L, Cornejo S, Kaplan F, Sweezey NB. Reduced viability of mice with lung epithelial-specific knockout of glucocorticoid receptor. Am J Respir Cell Mol Biol. 2010;43(5):599–606.
65. Habermehl D, Parkitna JR, Kaden S, Brügger B, Wieland F, Gröne HJ, Schütz G. Glucocorticoid activity during lung maturation is essential in mesenchymal and less in alveolar epithelial cells. Mol Endocrinol. 2011;25(8):1280–1288.
66. Bird AD, Choo YL, Hooper SB, McDougall AR, Cole TJ. Mesenchymal glucocorticoid receptor regulates the development of multiple cell layers of the mouse lung. Am J Respir Cell Mol Biol. 2014;50(2):419–428.
67. Li A, Hardy R, Stoner S, Tuckermann J, Seibel M, Zhou H. Deletion of mesenchymal glucocorticoid receptor attenuates embryonic lung development and abdominal wall closure. PLoS One. 2013;8(5):e63578.
68. Wüst S, van den Brandt J, Tischner D, Kleiman A, Tuckermann JP, Gold R, Lühder F, Reichardt HM. Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis. J Immunol. 2008;180(12):8434–8443.
69. Schweingruber N, Haine A, Tiede K, Karabinskaya A, van den Brandt J, Wüst S, Metselaar JM, Gold R, Tuckermann JP, Reichardt HM, Lühder F. Liposomal encapsulation of glucocorticoids alters their mode of action in the treatment of experimental autoimmune encephalomyelitis. J Immunol. 2011;187(8): 4310–4318.
70. Schweingruber N, Fischer HJ, Fischer L, van den Brandt J, Karabinskaya A, Labi V, Villunger A, Kretzschmar B, Huppke P, Simons M, Tuckermann JP, Flügel A, Lühder F, Reichardt HM. Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses. Acta Neuropathol. 2014;127(5):713–729.
71. Baschant U, Frappart L, Rauchhaus U, Bruns L, Reichardt HM, Kamradt T, Bräuer R, Tuckermann JP. Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells. Proc Natl Acad Sci USA. 2011;108(48): 19317–19322.
72. Guo L, Zheng Z, Ai J, Howatt DA, Mittelstadt PR, Thacker S, Daugherty A, Ashwell JD, Remaley AT, Li XA. Scavenger receptor BI and high-density lipoprotein regulate thymocyte apoptosis in sepsis. Arterioscler Thromb Vasc Biol. 2014;34(5):966–975.
73. + T cells. J Pathol. 2015;235(4):646–655.
74. Engler JB, Kursawe N, Solano ME, Patas K, Wehrmann S, Heckmann N, Lühder F, Reichardt HM, Arck PC, Gold SM, Friese MA. Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc Natl Acad Sci USA. 2017; 114(2):E181–E190.
75. + T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection. J Exp Med. 2013;210(10):1919–1927.
76. Li CC, Munitic I, Mittelstadt PR, Castro E, Ashwell JD. Suppression of dendritic cell-derived IL-12 by endogenous glucocorticoids is protective in LPS-induced sepsis. PLoS Biol. 2015; 13(10):e1002269.
77. Bhattacharyya S, Brown DE, Brewer JA, Vogt SK, Muglia LJ. Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood. 2007;109(10):4313–4319.
78. Preusch MR, Rattazzi M, Albrecht C, Merle U, Tuckermann J, Schütz G, Blessing E, Zoppellaro G, Pauletto P, Krempien R, Rosenfeld ME, Katus HA, Bea F. Critical role of macrophages in glucocorticoid driven vascular calcification in a mouse-model of atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28(12): 2158–2164.
79. Watson ML, Baehr LM, Reichardt HM, Tuckermann JP, Bodine SC, Furlow JD. A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure. Am J Physiol Endocrinol Metab. 2012; 302(10):E1210–E1220.
80. Braun TP, Szumowski M, Levasseur PR, Grossberg AJ, Zhu X, Agarwal A, Marks DL. Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle. PLoS One. 2014;9(9):e106489.
81. Braun TP, Grossberg AJ, Krasnow SM, Levasseur PR, Szumowski M, Zhu XX, Maxson JE, Knoll JG, Barnes AP, Marks DL. Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle. FASEB J. 2013;27(9):3572–3582.
82. Shimizu N, Maruyama T, Yoshikawa N, Matsumiya R, Ma Y, Ito N, Tasaka Y, Kuribara-Souta A, Miyata K, Oike Y, Berger S, Schütz G, Takeda S, Tanaka H. A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling. Nat Commun. 2015;6:6693.
83. Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp. 1932;50:137–195.
84. Mitra R. Adverse effects of corticosteroids on bone metabolism: a review. PM R. 2011;3(5):466–471, quiz 471.
85. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest. 1998;102(2):274–282.
86. Rauch A, Seitz S, Baschant U, Schilling AF, Illing A, Stride B, Kirilov M, Mandic V, Takacz A, Schmidt-Ullrich R, Ostermay S, Schinke T, Spanbroek R, Zaiss MM, Angel PE, Lerner UH, David JP, Reichardt HM, Amling M, Schütz G, Tuckermann JP. Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab. 2010;11(6):517–531.
87. Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ, Ross FP, Teitelbaum SL. Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest. 2006;116(8):2152–2160.
88. Clausen BE, Burkhardt C, Reith W, Renkawitz R, Förster I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8(4):265–277.
89. Brennan-Speranza TC, Henneicke H, Gasparini SJ, Blankenstein KI, Heinevetter U, Cogger VC, Svistounov D, Zhang Y, Cooney GJ, Buttgereit F, Dunstan CR, Gundberg C, Zhou H, Seibel MJ. Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Invest. 2012;122(11):4172–4189.
90. Filaretova L. Glucocorticoids are gastroprotective under physiologic conditions. Ther Adv Chronic Dis. 2011;2(5):333–342.
91. Reichardt SD, Weinhage T, Rotte A, Föller M, Oppermann M, Lühder F, Tuckermann JP, Lang F, van den Brandt J, Reichardt HM. Glucocorticoids induce gastroparesis in mice through depletion of L-arginine. Endocrinology. 2014;155(10):3899–3908.
92. Reichardt SD, Föller M, Rexhepaj R, Pathare G, Minnich K, Tuckermann JP, Lang F, Reichardt HM. Glucocorticoids enhance intestinal glucose uptake via the dimerized glucocorticoid receptor in enterocytes. Endocrinology. 2012;153(4):1783–1794.
93. Desarzens S, Faresse N. Adipocyte glucocorticoid receptor has a minor contribution in adipose tissue growth. J Endocrinol. 2016; 230(1):1–11.
94. Gesina E, Tronche F, Herrera P, Duchene B, Tales W, Czernichow P, Breant B. Dissecting the role of glucocorticoids on pancreas development. Diabetes. 2004;53(9):2322–2329.
95. Tronche F, Opherk C, Moriggl R, Kellendonk C, Reimann A, Schwake L, Reichardt HM, Stangl K, Gau D, Hoeflich A, Beug H, Schmid W, Schütz G. Glucocorticoid receptor function in hepatocytes is essential to promote postnatal body growth. Genes Dev. 2004;18(5):492–497.
96. Park YK, Ge K. Glucocorticoid receptor accelerates, but is dispensable for, adipogenesis. Mol Cell Biol. 2017;37(2):e00260-16.
97. Mueller KM, Hartmann K, Kaltenecker D, Vettorazzi S, Bauer M, Mauser L, Amann S, Jall S, Fischer K, Esterbauer H, Müller TD, Tschöp MH, Magnes C, Haybaeck J, Scherer T, Bordag N, Tuckermann JP, Moriggl R. Adipocyte glucocorticoid receptor deficiency attenuates aging- and HFD-induced obesity and impairs the feeding-fasting transition. Diabetes. 2017;66(2): 272–286.
98. de Kloet AD, Krause EG, Solomon MB, Flak JN, Scott KA, Kim DH, Myers B, Ulrich-Lai YM, Woods SC, Seeley RJ, Herman JP. Adipocyte glucocorticoid receptors mediate fat-to-brain signaling. Psychoneuroendocrinology. 2015;56:110–119.
99. Engblom D, Kornfeld JW, Schwake L, Tronche F, Reimann A, Beug H, Hennighausen L, Moriggl R, Schütz G. Direct glucocorticoid receptor–Stat5 interaction in hepatocytes controls body size and maturation-related gene expression. Genes Dev. 2007;21(10):1157–1162.
100. Opherk C, Tronche F, Kellendonk C, Kohlmüller D, Schulze A, Schmid W, Schütz G. Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes mellitus. Mol Endocrinol. 2004;18(6):1346–1353.
101. Van Bogaert T, Vandevyver S, Dejager L, Van Hauwermeiren F, Pinheiro I, Petta I, Engblom D, Kleyman A, Schütz G, Tuckermann J, Libert C. Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock. J Biol Chem. 2011;286(30):26555–26567.
102. He B, Cruz-Topete D, Oakley RH, Xiao X, Cidlowski JA. Human glucocorticoid receptor b regulates gluconeogenesis and inflammation in mouse liver. Mol Cell Biol. 2015;36(5):714–730.
103. Rose AJ, Berriel Díaz M, Reimann A, Klement J, Walcher T, Krones-Herzig A, Strobel O, Werner J, Peters A, Kleyman A, Tuckermann JP, Vegiopoulos A, Herzig S. Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor. Cell Metab. 2011;14(1):123–130.
104. Mueller KM, Kornfeld JW, Friedbichler K, Blaas L, Egger G, Esterbauer H, Hasselblatt P, Schlederer M, Haindl S, Wagner KU, Engblom D, Haemmerle G, Kratky D, Sexl V, Kenner L, Kozlov AV, Terracciano L, Zechner R, Schuetz G, Casanova E, Pospisilik JA, Heim MH, Moriggl R. Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Hepatology. 2011;54(4): 1398–1409.
105. Shteyer E, Liao Y, Muglia LJ, Hruz PW, Rudnick DA. Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice. Hepatology. 2004;40(6):1322–1332.
106. Bose SK, Hutson I, Harris CA. Hepatic glucocorticoid receptor plays a greater role than adipose GR in metabolic syndrome despite renal compensation. Endocrinology. 2016;157(12): 4943–4960.
107. Quinn MA, Cidlowski JA. Endogenous hepatic glucocorticoid receptor signaling coordinates sex-biased inflammatory gene expression. FASEB J. 2016;30(2):971–982.
108. Shiojiri N. Enzymo- and immunocytochemical analyses of the differentiation of liver cells in the prenatal mouse. J Embryol Exp Morphol. 1981;62:139–152.
109. Cascio S, Zaret KS. Hepatocyte differentiation initiates during endodermal-mesenchymal interactions prior to liver formation. Development. 1991;113(1):217–225.
110. Goodwin JE, Zhang J, Velazquez H, Geller DS. The glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension. Biochem Biophys Res Commun. 2010;394(2):266–271.
111. Kuppe C, van Roeyen C, Leuchtle K, Kabgani N, Vogt M, Van Zandvoort M, Smeets B, Floege J, Grone HJ, Moeller MJ. Investigations of glucocorticoid action in GN. J Am Soc Nephrol. 2017;28(5):1408–1420.
112. Hazra R, Upton D, Jimenez M, Desai R, Handelsman DJ, Allan CM. In vivo actions of the Sertoli cell glucocorticoid receptor. Endocrinology. 2014;155(3):1120–1130.
113. Zhao B, Choi JP, Jaehne M, Gao YR, Desai R, Tuckermann J, Zhou H, Handelsman DJ, Simanainen U. Glucocorticoid receptor in prostate epithelia is not required for corticosteroid-induced epithelial hyperproliferation in the mouse prostate. Prostate. 2014;74(10):1068–1078.
114. Nishimura K, Nonomura N, Satoh E, Harada Y, Nakayama M, Tokizane T, Fukui T, Ono Y, Inoue H, Shin M, Tsujimoto Y, Takayama H, Aozasa K, Okuyama A. Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. J Natl Cancer Inst. 2001;93(22):1739–1746.
115. Kach J, Long TM, Selman P, Tonsing-Carter EY, Bacalao MA, Lastra RR, de Wet L, Comiskey S, Gillard M, VanOpstall C, West DC, Chan WC, Griend DV, Conzen SD, Szmulewitz RZ. Selective glucocorticoid receptor modulators (SGRMs) delay castrate-resistant prostate cancer growth. Mol Cancer Ther. 2017;16(8): 1680–1692.
116. Wintermantel TM, Bock D, Fleig V, Greiner EF, Schütz G. The epithelial glucocorticoid receptor is required for the normal timing of cell proliferation during mammary lobuloalveolar development but is dispensable for milk production. Mol Endocrinol. 2005; 19(2):340–349.
117. Rabin D, Gold PW, Margioris AN, Chrousos GP. Stress and reproduction: physiologic and pathophysiologic interactions between the stress and reproductive axes. Adv Exp Med Biol. 1988; 245:377–387.
118. Whirledge SD, Oakley RH, Myers PH, Lydon JP, DeMayo F, Cidlowski JA. Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization. Proc Natl Acad Sci USA. 2015;112(49):15166–15171.
119. Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96(1): 23–43.
120. Bayo P, Sanchis A, Bravo A, Cascallana JL, Buder K, Tuckermann J, Schütz G, Pérez P. Glucocorticoid receptor is required for skin barrier competence. Endocrinology. 2008;149(3):1377–1388.
121. Sevilla LM, Latorre V, Sanchis A, Pérez P. Epidermal inactivation of the glucocorticoid receptor triggers skin barrier defects and cutaneous inflammation. J Invest Dermatol. 2013;133(2): 361–370.
122. Pérez P, Page A, Bravo A, Del Río M, Giménez-Conti I, Budunova I, Slaga TJ, Jorcano JL. Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor. FASEB J. 2001; 15(11):2030–2032.
123. Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R, Gass P, Schmid W, Herrlich P, Angel P, Schütz G. DNA binding of the glucocorticoid receptor is not essential for survival. Cell. 1998;93(4):531–541.
124. Sevilla LM, Bayo P, Latorre V, Sanchis A, Pérez P. Glucocorticoid receptor regulates overlapping and differential gene subsets in developing and adult skin. Mol Endocrinol. 2010;24(11):2166–2178.
125. Latorre V, Sevilla LM, Sanchis A, Pérez P. Selective ablation of glucocorticoid receptor in mouse keratinocytes increases susceptibility to skin tumorigenesis. J Invest Dermatol. 2013; 133(12):2771–2779.
126. Politch JA, Herrenkohl LR. Postnatal ACTH and corticosterone: effects on reproduction in mice. Physiol Behav. 1984;32(3): 447–452.
127. Dubey AK, Plant TM. A suppression of gonadotropin secretion by cortisol in castrated male rhesus monkeys (Macaca mulatta) mediated by the interruption of hypothalamic gonadotropin-releasing hormone release. Biol Reprod. 1985;33(2):423–431.
128. +/2 mice? Behav Brain Res. 2017;335:71–79.
129. Presman DM, Ogara MF, Stortz M, Alvarez LD, Pooley JR, Schiltz RL, Grøntved L, Johnson TA, Mittelstadt PR, Ashwell JD, Ganesan S, Burton G, Levi V, Hager GL, Pecci A. Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor. PLoS Biol. 2014;12(3):e1001813.
130. Jewell CM, Scoltock AB, Hamel BL, Yudt MR, Cidlowski JA. Complex human glucocorticoid receptor dim mutations define glucocorticoid induced apoptotic resistance in bone cells. Mol Endocrinol. 2012;26(2):244–256.
131. Zhang J, Ge R, Matte-Martone C, Goodwin J, Shlomchik WD, Mamula MJ, Kooshkabadi A, Hardy MP, Geller D. Characterization of a novel gain of function glucocorticoid receptor knock-in mouse. J Biol Chem. 2009;284(10):6249–6259.
132. Banuelos J, Shin SC, Lu NZ. A hotspot in the glucocorticoid receptor DNA-binding domain susceptible to loss of function mutation. Steroids. 2015;96:115–120.
133. Koper JW, van Rossum EF, van den Akker EL. Glucocorticoid receptor polymorphisms and haplotypes and their expression in health and disease. Steroids. 2014;92:62–73.
134. Galliher-Beckley AJ, Williams JG, Cidlowski JA. Ligand-independent phosphorylation of the glucocorticoid receptor integrates cellular stress pathways with nuclear receptor signaling. Mol Cell Biol. 2011;31(23):4663–4675.
135. DeMayo FJ, Spencer TE. CRISPR bacon: a sizzling technique to generate genetically engineered pigs. Biol Reprod. 2014;91(3):79.
136. Ma H, Marti-Gutierrez N, Park S-W, Wu J, Lee Y, Suzuki K, Koski A, Ji D, Hayama T, Ahmed R, Darby H, Van Dyken C, Li Y, Kang E, Park AR, Kim D, Kim S-T, Gong J, Gu Y, Xu X, Battaglia D, Krieg SA, Lee DM, Wu DH, Wolf DP, Heitner SB, Belmonte JCI, Amato P, Kim J-S, Kaul S, Mitalipov S. Correction of a pathogenic gene mutation in human embryos. Nature. 2017; 548(7668):413–419.