Not every postmenopausal woman with a low level of estrogen suffers from osteoporosis, and no correlation of bone density with serum estrogen level, but a significant correlation with adrenal androgens, is often noted. Vitamin D-3 has been reported to be osteoclastic in vitro, whereas the effectiveness of vitamin D-3 for the treatment of osteoporosis is clinically relevant. To study the roles of these factors in the development of 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)-10(-7) M transiently induced the expression and enzymatic activity of aromatase cytochrome P450 (P450(AROM)) in primary cultured osteoblasts, and the K-m value for androstenedione (4.7 +/- 2.9 nM) was lower than that in adipose tissue and skin. Human osteoblasts showed a promoter specificity different from that found in other tissues. 1,25-Dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] alone did not induce aromatase activity, but enhanced and maintained glucocorticoid-induced P450(AROM) gene expression. This synergistic effect was not observed by other sex steroids or retinoic acids. The enhancement of P450(AROM) activity by 1,25-(OH)(2)D-3 varied from 0.94-fold (no enhancement) to 2.40-fold (maximal enhancement) among the individual human osteoblasts examined, but the magnitude of the enhancement was significantly correlated with the level of vitamin D receptor messenger RNA (P < 0.05). Cycloheximide did not abolish the synergistic effect of 1,25-(OH)(2)D-3, suggesting that de novo protein synthesis is not required for the synergism with 1,25-(OH)(2)D-3. These results suggest that bone tissue can synthesize estrogen from adrenal androgens by a unique aromatase activity depending on the level of vitamin D receptor expressed.
