RU486 Reversal of Cortisol Repression of 1,25-Dihydroxyvitamin D&amp;lt;sub&amp;gt;3&amp;lt;/sub&amp;gt; Induction of the Human Osteocalcin Promoter

Nigel A Morrison

doi:10.4236/ojemd.2013.31009

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.

Highlights

The compound 11β-[p-(Dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one, known as RU486 or mifepristone, is a synthetic anti-progesterone compound that has strong anti-glucocorticoid properties [1] and is used occasionally for treatment for Cushing’s syndrome, a disease characterized by high circulating corticosteroid levels [2,3]
In this paper we show that cortisol, a natural glucocorticoid, represses both basal and vitamin D induced activity of the human osteocalcin promoter
The three glucocorticoids resulted in sensitive repression of osteocalcin basal promoter activity in a manner consistent with dexamethasone having a higher affinity for the glucocorticoid receptor (GR) than cortisol or corticosterone

Summary

Introduction

The compound 11β-[p-(Dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one, known as RU486 or mifepristone, is a synthetic anti-progesterone compound that has strong anti-glucocorticoid properties [1] and is used occasionally for treatment for Cushing’s syndrome, a disease characterized by high circulating corticosteroid levels [2,3]. One of the clinical manifestations of corticosteroid excess is the development of osteopenia and osteoporosis [4,5]. A humoral marker of bone formation, the protein osteocalcin, is substantially reduced in corticosteroid osteoporosis [6]. Glucocorticoids are differentiation stimulators in cultured osteoblasts [5] and result in more mineralized matrix over reasonable time spans, using in vitro cell models [6]. Glucocorticoids can repress the ability of vitamin D3 metabolites to induce the osteocalcin gene in osteoblast-like cells in culture, presumably mimicking the situation of repressed osteocalcin in vivo [7]. Longerterm effects of glucocorticoids in vivo create negative effects in bone, including inhibition of osteoblast proliferation [8] and apoptosis of both osteoblasts and osteocytes [9]. Brennan-Speranza et al [10], using osteoblast-specific gene knockout, show that the negative effects of glucocorticoids on energy balance in the entire body are mediated through osteoblast glucocorticoid receptor (GR), making the mode of action of anti-glucocorticoids in osteoblasts of particular relevance to glucocorticoid action in general

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Conclusion