Glucocorticoids Impair Bone Resorptive Activity and Viability of Osteoclasts Disaggregated from Neonatal Rat Long Bones*

Abstract

It is generally believed that glucocorticoids cause osteoporosis through a combination of decreased bone formation and increased bone resorption. However, the direct effect of glucocorticoids on osteoclasts has not been determined. We therefore tested the effects of hydrocortisone and dexamethasone on bone resorption by osteoclasts disaggregated from neonatal rat long bones. Hydrocortisone and dexamethasone caused a dose-dependent inhibition of osteoclastic bone resorption in the range 10(-7) to 10(-5) M, and 10(-9) to 10(-6) M, respectively, at concentrations likely to occur during therapy and disease. Inhibition of bone resorption was found to be associated with impaired osteoclast survival: osteoclast numbers were reduced to approximately 25% of control values by 10(-6) M hydrocortisone and 10(-7) M dexamethasone. Osteoclast cytotoxicity by glucocorticoids was completely antagonized by progesterone, which itself had no effect on osteoclast survival. Analysis of the time course of these inhibitory effects showed a nonsignificant reduction in survival by 6 h and marked inhibition of survival by 12 h. We could detect no specific changes in osteoclast morphology in association with this impaired viability. The relative potencies of the glucocorticoids for impairment of osteoclast viability was similar to their relative affinities for binding the glucocorticoid receptor, and this, together with inhibition by progesterone, suggests a receptor-mediated mechanism. Such a receptor-mediated cytotoxic action of glucocorticoids has only previously been reported with lymphoid cells. The sensitivity of osteoclasts to the lethal effects of glucocorticoids suggests that glucocorticoids may have a role in physiology as inhibitors of osteoclastic bone resorption.

Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle

“…Metabolic activity was unaffected when OCs were seeded on bone in the presence of 1.6 mM prednisolone but was negatively affected when seeded on plastic, indicating cell death (data not shown), which has been described previously. (12,14) Taken together, these observations strongly suggest that GCs directly affect OC resorptive behavior. Although the total number of resorptive events and TRACP activity after 72 hours was negatively affected by GCs, they were deeper and appeared more frequently as trenches, and OC collagenolytic activity was found to be elevated more.…”

“…Our study is in accordance with this absence of effect on resorption area generated by human OCs, (13,15) but not with others, where less purified mouse or rat OCs were used and where GCs rather decreased total resorption areas. (10,12,14) We speculate that this decrease could be due to use of OCs from other animal species or to the presence of other cell types.…”

“…Increased OC survival is stressed in several studies, (9)(10)(11) but according to other studies, OC survival is decreased by GCs or not affected. (12)(13)(14) Enhanced OC differentiation also has been proposed, (13,15,16) but others found that OC differentiation was decreased by GCs or not affected. (10,17,18) One would expect that besides survival and differentiation, the resorptive activity of existing OCs is also stimulated by GCs because of the very early increase in bone-resorption markers induced by GCs in patients.…”

“…Instead, primary OCs isolated from rat bones eroded the surfaces of bone slices less extensively in the presence of high-dose GC. (12,14) So also did OCs generated from mouse bone marrow cells cultured in the presence of macrophage colonystimulating factor (M-CSF) and receptor-activator of NF-kB ligand (RANKL), (10) whereas human OCs generated from peripheral blood mononuclear cells in the presence of the same cytokines and seeded on bone slices did not respond to high-dose GCs. (13,15) This absence of direct stimulation of the resorptive activity of OCs in vitro would fit an indirect mechanism of action of GCs on OCs.…”

The systemic effect of intraarticular administration of corticosteroid on markers of bone formation and bone resorption in patients with rheumatoid arthritis

“…DeFranco et a1 suggested that corticosteroid can increase the activity of existing osteoclasts while inhibiting the production of new osteoclasts (32). Others have found that both hydrocortisone and dexamethasone decreased the activity of isolated osteoclasts (33,34). Corticosteroid has also been shown to induce apoptosis, or programmed cell death, in many cells (35).…”