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Glucocorticoids impair bone resorptive activity and viability of osteoclasts disaggregated from neonatal rat long
1Department of Histopathology, St George's Hospital Medical School, London, United Kingdom.
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.
Insights
Glucocorticoids, like hydrocortisone and dexamethasone, directly inhibit bone resorption by osteoclasts, a key cell in bone remodeling. This effect is mediated by a receptor-dependent mechanism, reducing osteoclast survival.
Area of Science:
- Endocrinology
- Bone Biology
- Cell Biology
Background:
- Glucocorticoids are known to cause osteoporosis by affecting bone formation and resorption.
- The direct impact of glucocorticoids on osteoclasts, the cells responsible for bone resorption, remains unclear.
Purpose of the Study:
- To investigate the direct effects of hydrocortisone and dexamethasone on osteoclast bone resorption.
- To determine the mechanism underlying glucocorticoid-induced changes in osteoclast activity and survival.
Main Methods:
- Osteoclasts were disaggregated from neonatal rat long bones.
- Treated osteoclasts with varying concentrations of hydrocortisone and dexamethasone.
- Assessed bone resorption, osteoclast survival, and morphology.
- Investigated the role of progesterone as an antagonist.
Main Results:
- Hydrocortisone and dexamethasone demonstrated dose-dependent inhibition of osteoclastic bone resorption.
- Glucocorticoid treatment significantly reduced osteoclast numbers, indicating impaired survival.
- Progesterone antagonized the cytotoxic effects of glucocorticoids on osteoclasts, suggesting a receptor-mediated pathway.
- Inhibitory effects on survival were observed within 12 hours, without significant morphological changes.
Conclusions:
- Glucocorticoids directly inhibit osteoclast bone resorption and survival through a receptor-mediated mechanism.
- Osteoclasts exhibit sensitivity to the cytotoxic effects of glucocorticoids, similar to lymphoid cells.
- These findings suggest a potential physiological role for glucocorticoids in regulating bone resorption by inhibiting osteoclasts.