Impaired estrogen sensitivity in bone by inhibiting both estrogen receptoralpha and beta pathways

Although it is well established that estrogen deficiency causes osteoporosi s among the postmenopausal women, the involvement of estrogen receptor (ER) in its pathogenesis still remains uncertain. In the present study, we have generated rats harboring a dominant negative ER alpha, which inhibits the actions of not only ER alpha but also recently identified ER beta. Contrary to our expectation, the bone mineral density (BMD) of the resulting transg enic female rats was maintained at the same level with that of the wild-typ e littermates when sham-operated. In addition, ovariectomy-induced bone los s was observed almost equally in both groups. Strikingly, however, the BMD of the transgenic female rats, after ovariectomized, remained decreased eve n if 17 beta-estradiol (E-2) was administrated, whereas, in contrast, the d ecrease of littermate BMD was completely prevented by E-2. Moreover, bone h istomorphometrical analysis of ovariectomized transgenic rats revealed that the higher rates of bone turnover still remained after treatment with E-2. These results demonstrate that the prevention from the ovariectomy-induced bone loss by estrogen is mediated by ER pathways and that the maintenance of BMD before ovariectomy might be compensated by other mechanisms distinct from ER alpha and ER beta pathways.