Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization
Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization
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DOI：
10.1172/jci45890
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发表时间：
2012-05-01
影响因子：
15.9
通讯作者：
Carmeliet, Geert
中科院分区：
文献类型：
--
作者：
Lieben, Liesbet;Masuyama, Ritsuko;Carmeliet, Geert
血清钙水平由一个集成的激素控制系统严格控制，该系统涉及活性维生素D[1，25(OH)(2)D]，当肠道钙吸收减少时，它可以引起骨骼中的钙动员。然而，骨骼适应的特征仍然很差。为了深入了解这些问题，我们分析了肠道和成熟成骨细胞中特定的维生素D受体(VDR)失活对钙和骨稳态的影响。我们在这里报道，肠道特异性VDR基因敲除小鼠肠道钙吸收减少导致骨骼钙水平严重下降，以确保血清钙的正常水平。此外，1，25(OH)(2)D水平升高不仅刺激骨转换，导致骨量减少，而且抑制骨基质矿化。这导致广泛的类骨质增多症，骨细胞周围，以及整个骨皮质的矿化减少，这可能是导致骨折增加的原因之一。从机制上讲，成骨细胞VDR信号通过直接刺激编码矿化抑制物基因的转录来抑制骨骼中的钙掺入。去除骨骼VDR信号可以阻止这种从骨骼到血清的钙转移，从而更好地保存骨量和矿化。这些结果表明，在小鼠中，保持正常的血钙水平优先于骨骼的完整性，为了减少骨骼钙的储存，1，25(OH)(2)D不仅增加了骨中钙的释放，而且还抑制了钙在骨中的掺入。
Serum calcium levels are tightly controlled by an integrated hormone-controlled system that involves active vitamin D [1,25(OH)(2)D], which can elicit calcium mobilization from bone when intestinal calcium absorption is decreased. The skeletal adaptations, however, are still poorly characterized. To gain insight into these issues, we analyzed the consequences of specific vitamin D receptor (Vdr) inactivation in the intestine and in mature osteoblasts on calcium and bone homeostasis. We report here that decreased intestinal calcium absorption in intestine-specific Vdr knockout mice resulted in severely reduced skeletal calcium levels so as to ensure normal levels of calcium in the serum. Furthermore, increased 1,25(OH)(2)D levels not only stimulated bone turnover, leading to osteopenia, but also suppressed bone matrix mineralization. This resulted in extensive hyperosteoidosis, also surrounding the osteocytes, and hypomineralization of the entire bone cortex, which may have contributed to the increase in bone fractures. Mechanistically, osteoblastic VDR signaling suppressed calcium incorporation in bone by directly stimulating the transcription of genes encoding mineralization inhibitors. Ablation of skeletal Vdr signaling precluded this calcium transfer from bone to serum, leading to better preservation of bone mass and mineralization. These findings indicate that in mice, maintaining normocalcemia has priority over skeletal integrity, and that to minimize skeletal calcium storage, 1,25(OH)(2)D not only increases calcium release from bone, but also inhibits calcium incorporation in bone.