Skeletal changes in transgenic male mice expressing human cytochrome p450 aromatase.

摘要

In this study, we showed that overexpressing P450 aromatase in male mice can increase bone mass and strengthen the tibia. Probably as a result of the action of products of local estrogen biosynthesis at different stages of life, the increased bone mass in young mice was induced by decreased bone turnover, but in aged animals, it was induced by increased bone formation. INTRODUCTION: To understand the skeletal responses to the testosterone/estrogen balance, especially to excess estrogen produced by extragonadal biosynthesis, we investigated the bone changes in transgenic mice overexpressing human aromatase. MATERIALS AND METHODS: Sixty-one young (40 days) and 25 aged (9 months) transgenic and wildtype (WT) mice were used. Bone samples were analyzed using pQCT, histomorphometry, and mechanical testing. Concentrations of testosterone (T) and estradiol (E(2)) were measured in serum and testicular interstitial fluid. RESULTS AND CONCLUSIONS: Young P450 aromatase-positive (AROM(+)) mice had much higher trabecular BMD in the proximal tibia than WT mice, and the tissue area was significantly smaller in the former. Histomorphometric data further showed that the longitudinal growth rate of the tibia was decreased in AROM(+) mice, and the bone formation rate (BFR) was decreased in trabecular bone and periosteum. All the changes were more striking in males than in females. Aged male AROM(+) mice showed similar changes in trabecular bone as young animals, but their BFR was obviously increased. Another dramatic change was in the tibias of aged AROM(+) mice: length was shorter (-23.2%), whereas ash weight was much heavier (+24.0%), and bending strength was markedly higher (+21.2%) compared with WT mice. The concentration of T was decreased in both serum and testicular interstitial fluid in young AROM(+) mice versus WT animals; E(2) levels were increased only in the testes of young AROM(+) mice. However, in aged AROM(+) mice, the levels of T and E(2) were highly increased in both serum and testis versus WT animals. These results are in agreement with the suggestion that enhanced production of estrogen from testosterone in the peripheral tissues as a result of aromatase action can affect skeletal growth and strengthen bone in males. The results also suggest a marked difference in response between femur and tibia.