Endocrine Abstracts (2003) 6 S20

11beta-hydroxysteroid dehydrogenase type 1: a prereceptor regulator of glucocorticoids in bone

M Hewison MS Cooper and PM Stewart

Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK

Glucocorticoids have potent but paradoxical effects on bone. In vitro they are required for the differentiation of osteoblasts but in excess can cause suppression of the mature osteoblast phenotype by reducing proliferation and inducing apoptosis. In vivo, glucocorticoids are anabolic at physiological concentrations, but in excess have an adverse effect on the skeleton most clearly seen in steroid-induced osteoporosis. We have postulated that this paradox may be resolved by localised expression of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in bone. Specifically by acting as an amplifier of glucocorticoid action, particularly in bone forming osteoblasts, 11beta-HSD1 may act as a prereceptor or autocrine mechanism maintaining a balance between positive and negative effects of glucocorticoids on the skeleton. Analysis of primary human tissue has shown that 11beta-HSD1 is well expressed in osteoblasts and in some osteoclasts and the enzyme activity is predominantly reductase. This includes conversion of cortisone to cortisol but synthetic therapeutic corticosteroids such as prednisone are also activated with equal affinity. Expression and activity of 11beta-HSD1 in osteoblasts is enhanced by inflammatory cytokines and by pre-treatment with glucocorticoids. Furthermore, clinical studies have shown that 11beta-HSD1 activity in osteoblastic cells correlates positively with the age of the bone sample donor. Collectively these observations have emphasised the potential impact of 11beta-HSD1 on both senile and steroid-induced osteoporosis. Finally, changes in biochemical parameters of bone following the ingestion of oral prednisolone have been related to endogenous pre-treatment levels of 11beta-HSD1 activity, suggesting that the enzyme may provide a novel predictive marker in the pathogenesis of steroid-induced osteoporosis.

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