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 in-duced activity of the human osteocalcin promoter. Furthermore, we address the specific question as to whether the an-ti-progestin anti-glucocorticoid RU486 is able to antagonize the inhibitory effect of cortisol on osteocalcin gene expres-sion. We show that RU486 has agonist activity alone, in that it is able to repress the basal promoter activity of the os-teocalcin gene and antagonist activity, reversing incompletely the cortisol mediated repression of 1,25-dihydroxyvita-min D3 induction.