A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice.
A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice.
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DOI：
10.1172/jci17246
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发表时间：
2003-05
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通讯作者：
N. Sims;P. Clément-Lacroix;D. Minet;C. Fraslon-Vanhulle;M. Gaillard-Kelly;M. Resche-Rigon;R. Baron
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文献类型：
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作者：
N. Sims;P. Clément-Lacroix;D. Minet;C. Fraslon-Vanhulle;M. Gaillard-Kelly;M. Resche-Rigon;R. Baron
虽然雌二醇在维持骨量方面的作用已得到充分证实，但雌二醇受体ER α和ER β以及雄激素受体（AR）的相对作用仍存在争议。为了确定ER α介导、ER β介导和非ER介导的机制在维持骨量中的作用，在ER敲除小鼠中研究了性腺切除术和雌二醇治疗。雌激素治疗卵巢切除ER α（-/-）小鼠未能防止骨丢失，排除了雌二醇通过非ER信号通路对骨的显着影响。相反，雌二醇阻止ER β（-/-）小鼠卵巢切除术诱导的骨丢失，与WT雄性和雌性小鼠相同，表明ER α是雌二醇在骨中作用的主要介质。雌激素受体α（-/-）小鼠的骨组织对雌激素无反应，提示雌激素不能通过AR保护体内骨量。与雌性ER alpha（-/-）和雄性ER alpha（-/-）小鼠相反，雌性ER alpha（-/-）小鼠部分地受到雌二醇对卵巢切除术诱导的骨丢失的保护，证实ER beta介导骨中的雌二醇作用，但仅在雌性中，并且效力低于ER alpha。我们得出结论，ER α是雌、雄小鼠骨中雌二醇保护功能的主要效应子，在其缺失的情况下，AR不足以介导这种反应。
Although the role of estradiol in maintaining bone mass is well established, the relative contributions of the estradiol receptors ERalpha and ERbeta and of the androgen receptor (AR) remain controversial. To determine the role of ERalpha-mediated, ERbeta-mediated, and non-ER-mediated mechanisms in maintaining bone mass, gonadectomy and estradiol treatment were studied in ER-knockout mice. Estradiol treatment of ovariectomized ERalphabeta(-/-) mice failed to prevent bone loss, precluding significant effects of estradiol on bone through non-ER-signaling pathways. In contrast, estradiol prevented ovariectomy-induced bone loss in ERbeta(-/-) mice, as in WT males and females, indicating that ERalpha is the major mediator of estradiol effects in bone. No response of bone to estradiol was detected in orchidectomized ERalpha(-/-) mice, suggesting estradiol cannot protect bone mass via the AR in vivo. In contrast to female ERalphabeta(-/-) and male ERalpha(-/-) mice, female ERalpha(-/-) mice were partially protected against ovariectomy-induced bone loss by estradiol, confirming that ERbeta mediates estradiol effects in bone, but only in females and with a lower efficacy than ERalpha. We conclude that ERalpha is the main effector of estradiol's protective function in bone in both male and female mice, and that, in its absence, AR is not sufficient to mediate this response.