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Differential Skeletal Susceptibility to Glucocorticoids

المؤلف:  Wass, J. A. H., Arlt, W., & Semple, R. K. (Eds.).

المصدر:  Oxford Textbook of Endocrinology and Diabetes

الجزء والصفحة:  3rd edition , p790

2026-07-21

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Individual susceptibility to glucocorticoids varies considerably, possibly because of differences in the absorption, distribution, or metabolism of the steroid, or because of differences in the number and affinity of glucocorticoid receptors. Polymorphisms of the glucocorticoid receptor gene are associated with differences in BMD and body composition. An attractive explanation to account for interindividual variability among those exposed to glucocorticoids is related to peripheral enzymes that interconvert active and inactive glucocorticoid molecules. 11- βHSD regulate the inter conversion of the inactive hormone cortisone and hormonally active cortisol. This enzyme plays a critical role in the regulation of glucocorticoid activity. Two distinct 11- βHSD enzymes have been described in humans. 11- βHSD type 2 is expressed in tissues with high levels of glucocorticoid receptors, such as liver and adipose tissue, and acts as an inactivating enzyme by converting cortisol to cortisone. This enzyme was identified also in rat and human osteosarcoma cells where glucocorticoid inactivation by this mechanism was demonstrated. In contrast, 11- βHSD type 1 is primarily a glucocorticoid activator, converting cortisone to cortisol. This enzyme is widely expressed in target tissues of glucocorticoid action, including bone. The activity of 11- βHSD type- 1 and its potential to generate cortisol from cortisone in human osteoblasts is increased by pro- inflammatory cytokines and by glucocorticoids. These effects of glucocorticoids appear to be mediated by the C/ EBP family of transcription factors. An inverse relationship between 11- βHSD type 1 activity and osteoblast differentiation appears to exist, although mice with targeted deletions of 11- βHSD type- 1 do not develop a skeletal phenotype. An increase of 11- βHSD type 1 activity occurs with ageing, possibly providing an explanation for the enhanced glucocorticoid effects in the skeleton of elderly subjects.