Recycling glucocorticoids: therapeutic implications of the 11β-HSD1 enzyme system

Endogenous glucocorticoids and commonly used oral glucocorticoids have the property of existing in an inactive and active form in vivo. The inactive form can be converted back to the active form, or 'recycled' in cells and tissues that express the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. This recycling provides an important contribution to the action of glucocorticoids. This review examines the literature relating to the importance of 11β-HSD1 activity during glucocorticoid treatment, with an emphasis on studies examining bone and joint disease and the ability of glucocorticoids to suppress inflammatory damage in models of arthritis. Animal models with global or selective deletion of 11β-HSD1 have determined the extent to which this recycling is important in normal physiology and during treatment with oral glucocorticoids. These studies demonstrate that 11β-HSD1-mediated recycling of inactive glucocorticoids has a substantial action and indeed is responsible for the majority of the effects of orally administered glucocorticoids on a range of tissues. Importantly, the anti-inflammatory actions of glucocorticoids appear largely through this mechanism such that mice that lack 11β-HSD1 are resistant to the anti-inflammatory actions of glucocorticoids. The recognition that to a large extent the circulating inactive counterpart of these glucocorticoids is more important to anti-inflammatory effects than the active glucocorticoid presents novel opportunities to more selectively target glucocorticoids to tissues or to reduce the likely side effects.