Treatment with an active vitamin D analogue blocks hypothalamic dysfunction-induced bone loss in mice
Treatment with an active vitamin D analogue blocks hypothalamic dysfunction-induced bone loss in mice
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活性维生素 D 类似物治疗可阻止小鼠下丘脑功能障碍引起的骨质流失
DOI：
10.1016/j.bbrc.2021.01.026
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Miyamoto T
中科院分区：
文献类型：
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作者：
Ito E;Sato Y;Kobayashi T;Nakamura S;Kaneko Y;Soma T;Matsumoto T;Kimura A;Miyamoto K;Matsumoto H;Matsumoto M;Nakamura M;Sato K;Miyamoto T
雌激素缺乏症可由女性卵巢功能障碍引起。在这种情况下，骨质疏松症的潜在机制已在动物模型，如卵巢切除的小鼠和大鼠中进行了表征，尽管下丘脑功能障碍如何促进骨质疏松症仍不清楚。在这里，我们表明，促性腺激素释放激素拮抗剂（GnRHa）的管理显着降低子宫重量，下丘脑功能障碍的表现，并促进皮质骨和骨小梁的雌性小鼠在体内的损失。我们还报道了给予GnRHa的小鼠破骨细胞数量显著增加，并且转录因子缺氧诱导因子1 α（HIF 1 α）在这些破骨细胞中积累。我们之前曾报道过，用活性维生素D类似物ED 71（也称为艾地骨化醇）治疗小鼠可以抑制破骨细胞中HIF 1 α的积聚。我们在这里表明，在小鼠中，ED 71与GnRHa联合给药显著挽救了由GnRHa单独给药引起的皮质骨和骨小梁骨量减少。破骨细胞中GnRHa依赖性HIF 1 α的蓄积也被ED 71联合给药阻断。我们的结论是，下丘脑功能障碍促进破骨细胞中HIF 1 α的积累，并可能导致骨量减少。我们的结论是，ED 71治疗可以作为一种治疗选择，以对抗人类疾病。
Estrogen deficiency can be caused by ovarian dysfunction in females. Mechanisms underlying osteoporosis in this condition have been characterized in animal models, such as ovariectomized mice and rats, although it remains unclear how hypothalamic dysfunction promotes osteoporosis. Here, we show that administration of a gonadotropin-releasing hormone antagonist (GnRHa) significantly decreases uterine weight, a manifestation of hypothalamic dysfunction, and promotes both cortical and trabecular bone loss in female micein vivo. We also report that osteoclast number significantly increased in mice administered GnRHa, and that the transcription factor hypoxia inducible factor 1 alpha (HIF1α) accumulated in those osteoclasts. We previously reported that treatment of mice with the active vitamin D analogue ED71, also known as eldecalcitol, inhibited HIF1α accumulation in osteoclasts. We show here that in mice, co-administration of ED71 with GnRHa significantly rescued the reduced cortical and trabecular bone mass promoted by GnRHa administration alone. GnRHa-dependent HIF1α accumulation in osteoclasts was also blocked by co-administration of ED71. We conclude that hypothalamic dysfunction promotes HIF1α accumulation in osteoclasts and likely results in reduced bone mass. We conclude that treatment with ED71 could serve as a therapeutic option to counter osteoporotic conditions in humans.