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首页> 外文期刊>American Journal of Physiology >The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice
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The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice

机译：雌激素受体-α及其激活功能-1在雌性小鼠生长板闭合中的作用

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High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-alpha stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERa and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERa (ERalpha~(-/-)) or ERalphaAF-1 (ERaAF-1~0) were evaluated. Old (16- to 19-mo-old) female ERalpha~(-/-) mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild- type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERalphaAF-1~0 mice (tibia: -4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERalphaAF-~0 mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERalpha~(-/-) mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERalpha or aromatase. In contrast, ERalphaAF-1 deletion results in a hyperactive ERa, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERa that do not require AF-1 and that ERalphaAF-1 opposes growth plate closure.
机译：青春期后期的高雌二醇水平会导致生长板封闭，从而使人的生长停止。在小鼠中，性成熟后生长板不会融合，但是老年小鼠显示出纵向骨生长减少，大剂量雌二醇治疗会导致生长板闭合。雌激素受体（ER）-α通过两个激活功能（AFs）AF-1和AF-2刺激基因转录。为了评估ERa及其AF-1在年龄依赖性减少纵向骨生长和生长板闭合中的作用，对具有ERa（ERalpha〜（-/-））或ERalphaAF-1（ERaAF-1〜0）失活的雌性小鼠）进行了评估。老（16至19个月大）雌性ERalpha〜（-/-）小鼠表现出持续的大量纵向骨生长，从而导致更长的骨骼（胫骨：+ 8.3％，P <0.01）与生长板高度增加相关（+与野生型（WT）小鼠相比为18％，P <0.05）。相反，老年ERalphaAF-1〜0小鼠的纵向骨生长停止了（胫骨：-4.9％，P <0.01）。重要的是，在所有旧的ERalphaAF-〜0小鼠中，胫骨近端生长板均已关闭，而在所有WT小鼠中均已打开。封闭生长板与生长板中软骨细胞增殖和凋亡之间的平衡显着改变有关。总之，老年雌性ERalpha〜（-/-）小鼠显示出延长的纵向骨生长，与增加的生长板高度有关，类似于具有ERalpha或芳香酶失活突变的患者的生长表型。相反，ERalphaAF-1缺失会导致ERa过度活跃，从而改变软骨细胞的增殖/凋亡平衡，从而导致生长板封闭。这表明生长板关闭是由不需要AF-1的ERa功能诱导的，而ERalphaAF-1则与生长板关闭相反。

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