INHIBITORY EFFECT OF PHYSIOLOGICAL CONCENTRATIONS OF CORTISOL BUT NOT ESTRADIOL ON INTERLEUKIN (IL)-6 PRODUCTION BY HUMAN OSTEOBLAST-LIKE CELL LINES WITH DIFFERENT CONSTITUTIVE IL-6 EXPRESSION

Abstract

Estrogen deficiency and glucocorticoid excess are two well-known conditions that account for osteoporosis. Interleukin (IL)-6 plays an important role in bone resorption; both estrogens and glucocorticoids are credited with an inhibitory effect on osteoblast production of IL-6. The aim of the study was to investigate whether endogenous hormones, which lead to opposite changes in bone mass, have a common inhibitory effect upon constitutive and inducible IL-6 production by human osteoblast-like cells. We used two human osteosarcoma cell lines (MG-63 and Saos-2) with a different degree of differentiation and constitutive production of IL-6 [2587±536 (mean±SE) and 3.65±0.06pg/106cells, respectively]. We examined the effects of physiological and supraphysiological concentrations of 17β-estradiol (E2) and cortisol on basal and IL-1β-induced IL-6 release in the medium. In all experimental conditions, cellular estrogen receptors (ERs) and glucocorticoid receptors (GRs) were measured by binding assay. Both MG-63 and Saos-2 cell lines had measurable GRs (106300±24996 and 18100±3215 binding sites/cell, respectively) and ERs (2197±377 and 1261±66.5 binding sites/cell, respectively). In MG-63 cells, cortisol treatment for 20h decreased both basal and IL-1β-induced IL-6 release in a dose-dependent manner; in Saos-2 cells the same effect was apparent for IL-1β-induced release. Mifepristone (RU-486) did function as partial agonist and antagonist of cortisol. At variance with cortisol, E2did not exert any effect on IL-6 secretion. Treatment with 1,25(OH)2D3increased by 100–200% ER concentrations, but did not change ineffectiveness of E2in modifying IL-6 production; furthermore, when E2was combined with cortisol, there was no additive effect on cortisol-induced inhibition. The dissociation between glucocorticoid and estrogen effects observed in these human cell lines is a sufficiently robust phenomenon to raise questions about the pathogenetic role of IL-6 in osteoporosis associated with estrogen deficiency. Conversely inhibition of osteoblast production of IL-6 may offer an explanation why bone resorption is not the dominant factor in the pathogenesis of glucocorticoid-induced osteoporosis.