Dehydroepiandrosterone (DHEA) as a possible source for estrogen formation in bone cells: correlation between bone mineral density and serum DHEA-sulfate concentration in postmenopausal women, and the presence of aromatase to be enhanced by 1,25-dihydroxyvitamin D3 in human osteoblasts.
A significant positive correlation between bone mineral density (BMD) and serum dehydroepiandrosterone sulfate (DHEA-S) was found in 120 postmenopausal women (51-99 years old) but no correlation was seen between BMD and serum estradiol. In subset analysis, strong positive correlation of serum DHEA-S and estrone with BMD was observed in postmenopausal women aged less than 69 years old. To study a possible role of DHEA-S in preventing osteoporosis, we characterized aromatase activity converting androgens to estrogens in human osteoblasts, because postmenopausal women maintain considerable levels of adrenal androgens. Glucocorticoids at 10(-9) to 10(-7) M induced transiently the expression of and the enzymatic activity of aromatase cytochrome P450 (P450AROM) in primary cultured osteoblasts. 1,25-Dihydroxyvitamin D3 (1,25-(OH)(2)D(3)) alone did not induce the aromatase activity, but enhanced and maintained the glucocorticoid-induced P450AROM gene expression. Analysis of the activity of P450AROM gene 1b (I.4) promoter, which is used dominantly in human osteoblasts, indicated that the region from -888 bp to -500 bp, which does not contain a typical vitamin D responsive element, is responsible for the enhancing effect of 1,25-(OH)(2)D(3). These results may suggest that adrenal androgen, DHEA, is converted to estrone in osteoblast by P450AROM, which is positively regulated by glucocorticoid and 1,25-(OH)(2)D(3), and is important in maintaining BMD in the sixth to the seventh decade, after menopause.
Takayanagi
Ryoichi
R
Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Japan. takayana@geriat.med.kyushu-u.ac.jp
Goto
Kiminobu
K
Suzuki
Shizu
S
Tanaka
Seiichi
S
Shimoda
Seiko
S
Nawata
Hajime
H
D015650:24,25-Dihydroxyvitamin D 3 / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D015519:Bone Density; D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000097:blood / Q000378:metabolism*; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood*; D003907:Dexamethasone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000166:cytology; D006801:Humans; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D017698:Postmenopause / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014212:Tretinoin / Q000494:pharmacology
D004967:Estrogens; D015650:24,25-Dihydroxyvitamin D 3; D003687:Dehydroepiandrosterone; D004958:Estradiol; D014212:Tretinoin; D019314:Dehydroepiandrosterone Sulfate; D003907:Dexamethasone; D001141:Aromatase; D002117:Calcitriol