Mineralization and Bone Resorption Are Regulated by the Androgen Receptor in Male Mice
Mineralization and Bone Resorption Are Regulated by the Androgen Receptor in Male Mice
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DOI：
10.1359/jbmr.081217
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发表时间：
2009-04-01
影响因子：
6.2
通讯作者：
Davey, Rachel A.
中科院分区：
文献类型：
--
作者：
Chiang, Cherie;Chiu, Maria;Davey, Rachel A.
雄激素在骨骼生长和骨骼维持中起着关键作用，但其作用机制尚不清楚。为了解决这一问题，我们使用Cre/loxP系统(骨钙素-Cre AR基因敲除[mobl-Arkos])选择性地删除了终末分化的矿化成骨细胞中的雄激素受体(AR)。雄性MOBL-Arkos在6、12和24周龄时，由于骨小梁数量减少，与产仔对照组相比，股骨松质骨体积减少，这表明骨吸收增加。AR在矿化成骨细胞中的失活作用在6周龄的年轻突变小鼠中最为明显，此时骨转换率很高，骨小梁体积减少35%，皮质厚度减少，骨基质矿化异常，其特征是未矿化骨基质增加，矿化表面积减少。尽管成骨细胞活性出现了意想不到的补偿性增加，但MOBL-Arkos组的这种骨结构损伤在整个成年期持续存在。我们的发现表明，雄激素通过成骨细胞矿化中的AR调节骨吸收和骨基质合成与矿化的协调来维持骨，并且这一作用在骨量增加和骨改建高发期是最重要的。
Androgens play a key role in skeletal growth and bone maintenance; however, their mechanism of action remains unclear. To address this, we selectively deleted the androgen receptor (AR) in terminally differentiated, mineralizing osteoblasts using the Cre/loxP system in mice (osteocalcin-Cre AR knockouts [mOBL-ARKOs]). Male mOBL-ARKOs had decreased femoral trabecular bone Volume compared with littermate controls because of a reduction in trabecular number at 6, 12, and 24 wk of age, indicative of increased bone resorption. The effects of AR inactivation in mineralizing osteoblasts was most marked in the young mutant mice at 6 wk of age when rates of bone turnover are high, with a 35% reduction in trabecular bone volume, decreased cortical thickness, and abnormalities in the mineralization of bone matrix, characterized by increased unmineralized bone matrix and a decrease in the amount of mineralizing surface. This impairment in bone architecture in the mOBL-ARKOs persisted throughout adulthood despite an unexpected compensatory increase in osteoblast activity. Our findings show that androgens act through the AR in mineralizing osteoblasts to maintain bone by regulating bone resorption and the coordination of bone matrix synthesis and mineralization, and that this action is most important during times of bone accrual and high rates of bone remodeling.