Share This Article:

RU486 Reversal of Cortisol Repression of 1,25-Dihydroxyvitamin D3 Induction of the Human Osteocalcin Promoter

Abstract Full-Text HTML XML Download Download as PDF (Size:686KB) PP. 55-62
DOI: 10.4236/ojemd.2013.31009    3,350 Downloads   5,791 Views   Citations

ABSTRACT

In conditions of corticosteroid excess, such as Cushing’s syndrome, a reduction in serum osteocalcin is observed and bone loss occurs. The human osteocalcin gene is induced by 1,25-dihydroxyvitamin D3 derivatives and repressed by glucocorticoids. In this paper we show that cortisol, a natural glucocorticoid, represses both basal and vitamin D induced activity of the human osteocalcin promoter. Furthermore, we address the specific question as to whether the anti-progestin anti-glucocorticoid RU486 is able to antagonize the inhibitory effect of cortisol on osteocalcin gene expression. We show that RU486 has agonist activity alone, in that it is able to repress the basal promoter activity of the osteocalcin gene and antagonist activity, reversing incompletely the cortisol mediated repression of 1,25-dihydroxyvitamin D3 induction.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

N. A. Morrison, "RU486 Reversal of Cortisol Repression of 1,25-Dihydroxyvitamin D3 Induction of the Human Osteocalcin Promoter," Open Journal of Endocrine and Metabolic Diseases, Vol. 3 No. 1, 2013, pp. 55-62. doi: 10.4236/ojemd.2013.31009.

References

[1] I. Jung-Testas and E. E. Baulieu, “Inhibition of Glucocorticosteroid Action in Cultured L-929 Mouse Fibroblasts by RU 486, a New Anti-Glucocorticosteroid of High Affinity for the Glucocorticosteroid Receptor,” Experimental Cell Research, Vol. 147, No. 1, 1983, pp. 177-182. doi:10.1016/0014-4827(83)90282-3
[2] F. Castinetti, T. Brue and B. Conte-Devolx, “The Use of the Glucocorticoid Receptor Antagonist Mifepristone in Cushing's Syndrome,” Current Opinion in Endocrinology, Diabetes and Obesity, Vol. 19, No. 4, 2012, pp. 295-299.
[3] M. Fleseriu and S. Petersenn, “Medical Management of Cushing’s Disease: What Is the Future?” Pituitary, Vol. 15, No. 3, 2012, pp. 330-341. doi:10.1007/s11102-012-0397-5
[4] T. Mancini, M. Doga, G. Mazziotti and A. Giustina, “Cushing’s Syndrome and Bone,” Pituitary, Vol. 7, No. 4, 2004, pp. 249-252. doi:10.1007/s11102-005-1051-2
[5] G. Mazziotti, A. Angeli, J. P. Bilezikian, E. Canalis and A. Giustina, “Glucocorticoid-Induced Osteoporosis: An Update,” Trends in Endocrinology and Metabolism, Vol. 17, No. 4, 2006, pp. 144-149. doi:10.1016/j.tem.2006.03.009
[6] S. Minisola, R. D. Fiacco, S. Piemonte, M. Iorio, M. L. Mascia, F. Fidanza, C. Cipriani, I. Raso, M. L. Porfiri, C. M. Francucci, E. D’Erasmo and E. Romagnoli, “Biochemical Markers in Glucocorticoid-Induced Osteoporosis,” Journal of Endocrinological Investigation, Vol. 31, No. 7, 2008, pp. 28-32.
[7] N. A. Morrison, J. Shine, J. C. Fragonas, V. Verkest, M. L. McMenemy and J. A. Eisman, “1,25-Dihydroxy-vitamin D-Responsive Element and Glucocorticoid Repression in the Osteocalcin Gene,” Science, Vol. 246, No. 4934, 1989, pp. 1158-1161. doi:10.1126/science.2588000
[8] D. Hong, H. X Chen, H. Q. Yu, C. Wang, H. T. Deng, Q. Q. Lian and R. S. Ge, “Quantitative Proteomic Analysis of Dexamethasone-Induced Effects on Osteoblast Differentiation, Proliferation, and Apoptosis in MC3T3-E1 Cells Using SILAC,” Osteoporosis International, Vol. 22, No. 7, 2011, pp. 2175-2186. doi:10.1007/s00198-010-1434-8
[9] R. S. Weinstein, R. L. Jilka, A. M. Parfitt and S. C. Manolagas, “Inhibition of Osteoblastogenesis and Promotion of Apoptosis of Osteoblasts and Osteocytes by Glucocorticoids. Potential Mechanisms of Their Deleterious Effects on Bone,” Journal of Clinical Investigation, Vol. 102, No. 2, 1998, pp. 274-282. doi:10.1172/JCI2799
[10] T. C. Brennan-Speranza, H. Henneicke, S. J. Gasparini, K. I. Blankenstein, U. Heinevetter, V. C. Cogger, D. Svistounov, Y. Zhang, C. J. Cooney, F. Buttgereit, C. R. Dunstan, C. Gundberg, H. Zhou and M. J. Seibel, “Osteoblasts Mediate the Adverse Effects of Glucocorticoids on Fuel Metabolism,” Journal of Clinical Investigation, Vol. 122, No. 11, 2012, pp. 4172-4189. doi:10.1172/JCI63377
[11] N. C. Nicolaides, Z. Galata, T. Kino, G. P. Chrousos and E. Charmandari, “The Human Glucocorticoid Receptor: Molecular Basis of Biologic Function,” Steroids, Vol. 75, No. 1, 2010, pp. 1-12. doi:10.1016/j.steroids.2009.09.002
[12] P. E. Str?mstedt, L. Poellinger, J. A. Gustafsson and J. Carlstedt-Duke, “The Glucocorticoid Receptor Binds to a Sequence Overlapping the TATA Box of the Human Osteocalcin Promoter: A Potential Mechanism for Negative Regulation,” Molecular and Cellular Biology, Vol. 11, No. 6, 1991, pp. 3379-3383.
[13] M. Surjit, K. P. Ganti, A. Mukherji, T. Ye, G. Hua, D. Metzger, M. Li and P. Chambon, “Widespread Negative Response Elements Mediate Direct Repression by Agonist-Liganded Glucocorticoid Receptor,” Cell, Vol. 145, No. 2, 2011, pp. 224-241. doi:10.1016/j.cell.2011.03.027
[14] C. M. Gorman, B. H. Howard and R. Reeves, “Expression of Recombinant Plasmids in Mammalian Cells Is Enhanced by Sodium Butyrate,” Nucleic Acids Research, Vol. 11, No. 21, 1983, pp. 7631-7648. doi:10.1093/nar/11.21.7631
[15] M. J. Sleigh, “A Nonchromatographic Assay for Expression of the Chloramphenicol Acetyltransferase Gene in Eucaryotic Cells,” Analytical Biochemistry, Vol. 156, No. 1, 1986, pp. 251-256.
[16] J. Schug and G. C. Overton, “TESS: Transcription Element Search Software on the WWW. Technical Report CBIL-TR-1997-1001-v0.0,” Computational Biology and Informatics Laboratory, School of Medicine University of Pennsylvania, 1997. http://www.cbil.upenn.edu/tess
[17] S. E. Wardell, R. Narayanan, N. L. Weigel and D. P. Edwards, “Partial Agonist Activity of the Progesterone Receptor Antagonist RU486 Mediated by an Amino-Teminal Domain Coactivator and Phosphorylation of Serine400,” Molecular Endocrinology, Vol. 24, No. 2, 2010, pp. 335-345. doi:10.1210/me.2008-0081
[18] M. Schulz, M. Eggert, A. Baniahmad, A. Dostert, T. Heinzel and R. Renkawitz, “RU486-Induced Glucocorticoid Receptor Agonism Is Controlled by the Receptor N Terminus and by Corepressor Binding,” Journal of Biological Chemistry, Vol. 277, No. 29, 2002, pp. 26238-26243. doi:10.1074/jbc.M203268200
[19] L. J. Lewis-Tuffin, C. M. Jewell, R. J. Bienstock, J. B. Collins and J. A. Cidlowski, “Human Glucocorticoid Receptor Beta Binds RU-486 and Is Transcriptionally Active,” Molecular and Cellular Biology, Vol. 27, No. 6, 2007, pp. 2266-2282. doi:10.1128/MCB.01439-06
[20] T. D. Hinds Jr., S. Ramakrishnan, H. A. Cash, L. A. Stechschulte, G. Heinrich, S. M. Najjar and E. R. Sanchez, “Discovery of Glucocorticoid Receptor-Beta in Mice with a Role in Metabolism,” Molecular Endocrinology, Vol. 24, No. 9, 2010, pp. 1715-1727. doi:10.1210/me.2009-0411
[21] E. M. Czekanska, M. J. Stoddart, R. G. Richards and J. S. Hayes, “In Search of an Osteoblast Cell Model for in Vitro Research,” European Cells and Materials Journal, Vol. 24, 2012, pp. 1-17.
[22] N. Morrison and J. Eisman, “Role of the Negative Glucocorticoid Regulatory Element in Glucocorticoid Repression of the Human Osteocalcin Promoter,” Journal of Bone and Mineral Research, Vol. 8, No. 8, 1993, pp. 969-975. doi:10.1002/jbmr.5650080810

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.