Vitamin D Receptor in Osteoblasts Is a Negative Regulator of Bone Mass Control
Vitamin D Receptor in Osteoblasts Is a Negative Regulator of Bone Mass Control
复制标题
DOI：
10.1210/en.2012-1542
复制
发表时间：
2013-03-01
期刊：
影响因子：
4.8
通讯作者：
Imai, Yuuki
中科院分区：
文献类型：
--
作者：
Yamamoto, Yoko;Yoshizawa, Tatsuya;Imai, Yuuki
维生素D对骨骼健康的生理和有益作用已在哺乳动物中得到实验和临床证实。维生素D的活性形式[1 α，25(OH)(2)D-3]结合并激活其特定的核受体，维生素D受体（VDR）。活化的VDR通过刺激肠道钙吸收和肾脏钙再吸收来阻止钙从骨中的储存释放到血清中。然而，VDR在骨组织中的直接作用尚不清楚，因为血清Ca2+稳态是通过肾脏、肠道和骨骼严格调节的离子运输来维持的。此外，使用VDR敲除（VDR- ko, VDR-/-）小鼠的传统遗传方法无法识别VDR在骨骼中的作用，因为动物在钙代谢方面存在全身性缺陷。在这项研究中，我们报告了用Cre/loxP系统和常规VDR杂合子（VDR+/-）生成的系统性VDR杂合子KO （VDR+/L-）小鼠在放射学评估中显示骨量增加。由于矿物质代谢参数在两种类型的小鼠中都没有改变，这些骨骼表型暗示骨骼VDR在骨量调节中起作用。为了证实这一假设，用2.3 kb α 1(I)-胶原启动子- cre转基因小鼠生成成骨特异性VDR- ko （VDR Delta Ob/Delta Ob）小鼠。他们表现出骨量增加而没有任何矿物质代谢失调。虽然骨形成参数不受骨组织形态学测量的影响，但由于VDR Delta Ob/Delta Ob成骨细胞中核因子κ b配体受体激活剂（破骨细胞生成的重要分子）的表达减少，VDR Delta Ob/Delta Ob小鼠的骨吸收明显减少。这些发现表明，成骨细胞中的VDR是骨量控制的负调节因子。[中国医学杂志]，2013。
The physiological and beneficial actions of vitamin D in bone health have been experimentally and clinically proven in mammals. The active form of vitamin D [1 alpha,25(OH)(2)D-3] binds and activates its specific nuclear receptor, the vitamin D receptor (VDR). Activated VDR prevents the release of calcium from its storage in bone to serum by stimulating intestinal calcium absorption and renal reabsorption. However, the direct action of VDR in bone tissue is poorly understood because serum Ca2+ homeostasis is maintained through tightly regulated ion transport by the kidney, intestine, and bone. In addition, conventional genetic approaches using VDR knockout (VDR-KO, VDR-/-) mice could not identify VDR action in bone because of the animals' systemic defects in calcium metabolism. In this study, we report that systemic VDR heterozygous KO (VDR+/L-) mice generated with the Cre/loxP system as well as conventional VDR heterozygotes (VDR+/-)showed increased bone mass in radiological assessments. Because mineral metabolism parameters were unaltered in both types of mice, these bone phenotypes imply that skeletal VDR plays a role in bone mass regulation. To confirm this assumption, osteoblast-specific VDR-KO (VDR Delta Ob/Delta Ob) mice were generated with 2.3 kb alpha 1(I)-collagen promoter-Cre transgenic mice. They showed a bone mass increase without any dysregulation of mineral metabolism. Although bone formation parameters were not affected in bone histomorphometry, bone resorption was obviously reduced in VDR Delta Ob/Delta Ob mice because of decreased expression of receptor activator of nuclear factor kappa-B ligand (an essential molecule in osteoclastogenesis) in VDR Delta Ob/Delta Ob osteoblasts. These findings establish that VDR in osteoblasts is a negative regulator of bone mass control. (Endocrinology 154: 1008-1020, 2013)