The Role of 11 β-Hydroxysteroid Dehydrogenase in Central Obesity and Osteoporosis

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Abstract
Both central obesity and osteoporosis are common findings in states of glucocorticoid excess. In many tissues, including adipose tissue, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the inter-conversion of active glucocorticoid, cortisol (F) and inactive cortisone (E) and regulates exposure to the glucocorticoid receptor. As such, factors which regulate 11β-HSD1 are likely to have an important role in adipose tissue and bone physiology. Using primary cultures of human adipose stromal cells we have investigated the effect of various factors present within the adipocyte microenvironment for their effects on 11β-HSD1 expression. IGF-1 caused a dose dependant inhibition of 11β-HSD1 activity in both subcutaneous and omental stromal cells. Additionally, TNFα treatment increased 11β-HSD1 reductase activity and mRNA expression. In adult human bone, 11β-HSD1, but not 11β-HSD2, expression was demonstrated using enzyme activity studies, RT-PCR and immunohistochemistry. In contrast to liver and adipose tissues, where reductase activity predominates, both reductase and dehydrogenase activities of 11β-HSD1 were evident in bone chips and primary cultures of human osteoblasts The action of growth factors and cytokines on glucocorticoid sensitive tissues such as adipose tissue and bone may be mediated by modulation of local glucocorticoid metabolism at a pre-receptor level.