Expression and functional consequences of 11-beta-hydroxysteroid dehydrogenase activity in human bone

Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess, In several tissues, glucocorticoid action i s dependent upon the expression of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) Isozymes, which interconvert active cortisol (F) and inactive co rtisone (E), We previously demonstrated the expression of 11 beta-HSD isozy mes in human osteosarcoma cell lines, osteoblast cultures, and fetal bone. We now characterize 11 beta-HSD expression in adult human bone using specif ic antihuman 11 beta-HSD antibodies, riboprobes, and enzyme activity studie s. In addition, the effect of 11 beta-HSD on bone metabolism in vivo was as sessed using the 11 beta-HSD inhibitor carbenoxolone in eight normal male v olunteers, in fresh normal human bone tissue, both 11 beta-dehydrogenase (c ortisol-to-cortisone conversion) and reductase (cortisone-to-cortisol conve rsion) activities were demonstrated. There was considerable interindividual variation in the dehydrogenase, but not reductase, activity. In bone homog enates, activity was NADP-dependent with a K-m for F of 4.8 +/- 1.2 mu mol/ L, suggesting the presence of 11 beta-HSD1. This was confirmed by reverse t ranscription-polymerase chain reaction (RT-PCR) analysis. Immunohistochemis try and in situ hybridization studies demonstrated 11 beta-HSD1 isozyme exp ression in cells of the osteoblast lineage and in osteoclasts, The 11 beta- HSD2 isozyme was expressed, but only in osteoblasts and at a low level. Ing estion of 300 mg of carbenoxolone by eight normal volunteers for 7 days res ulted in a significant decrease in the bone resorption markers, pyridinolin e (Pyr) and deoxypyridinoline (DPyr) (change in urinary Pyr/creatinine -1.5 5 +/- 0.55 [mean +/- SE], for DPyr/creatinine -0.4 +/- 0.14 nmol/mmol; p < 0.05 for both), with no overall change in the bone formation markers C- and N-terminal propeptides of type I collagen (PICP and PINP). These data sugg est that local tissue metabolism of glucocorticoids is likely to be importa nt in determining the sensitivity of both osteoblasts and osteoclasts to gl ucocorticoids. In particular, variation in 11 beta-HSD isozyme expression a nd activity may explain individual variation in susceptibility to glucocort icoid-induced osteoporosis. (C) 2000 by Elsevier Science Inc. All rights re served.