Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development.
Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development.
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钙通道ORAI1的基因破坏会导致破骨细胞和成骨细胞分化的抑制，并损害骨骼发育。
DOI：
10.1038/labinvest.2012.72
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发表时间：
2012-07
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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钙信号在骨细胞的调节中起着核心作用，尽管有关通道的不确定性仍然存在。在之前的研究中，我们确定了钙通道Orai1是体外形成多核破骨细胞所必需的。为了确定钙释放激活钙电流的骨骼功能，我们将钙通道Orai1靶向缺失的小鼠与野生型窝鼠对照进行了比较，并在体外检测了Orai1抑制和未抑制的成骨细胞和破骨细胞前体的分化和功能。与体外实验结果一致，Orai1−/−小鼠缺乏多核破骨细胞。然而，他们并没有患上骨质疏松症。在Orai1 - / -小鼠中发现了表达破骨细胞产物的单核细胞，体外研究表明，当Orai1被抑制时，外周血单核细胞培养形成的单核破骨细胞样细胞对矿物质的吸收显著减少，但并非没有。在Orai1−/−小鼠中更突出的是骨减少和胎儿软骨保留。显微计算机断层扫描显示，与对照组相比，Orai1−/−动物的皮质骨化减少，小梁变薄；敲除组骨沉积明显减少。这表明Orai1在成骨细胞中有一个以前未被认识到的作用。Orai1 - / -和对照小鼠的成骨细胞和前体分析显示，表达碱性磷酸酶的成骨细胞显著减少。体外研究证实，抑制Orai1活性会损害人成骨细胞的分化和功能，支持Orai1在成骨细胞中的关键功能，以及它作为破骨细胞形成的调节剂的作用。
Calcium signaling plays a central role in the regulation of bone cells, though uncertainty remains with regard to the channels involved. In previous studies, we determined that the calcium channel Orai1 was required for the formation of multinucleated osteoclasts in vitro. To define the skeletal functions of calcium release-activated calcium currents, we compared mice with targeted deletion of the calcium channel Orai1 to wild-type littermate controls, and examined differentiation and function of osteoblast and osteoclast precursors in vitro with and without Orai1 inhibition. Consistent with in vitro findings, Orai1−/− mice lacked multinucleated osteoclasts. Yet they did not develop osteopetrosis. Mononuclear cells expressing osteoclast products were found in Orai1−/− mice, and in vitro studies showed significantly reduced, but not absent, mineral resorption by the mononuclear osteoclast-like cells that form in culture from peripheral blood monocytic cells when Orai1 is inhibited. More prominent in Orai1−/− mice was a decrease in bone with retention of fetal cartilage. Micro-computed tomography showed reduced cortical ossification and thinned trabeculae in Orai1−/− animals compared to controls; bone deposition was markedly decreased in the knock-out. This suggested a previously unrecognized role for Orai1 within osteoblasts. Analysis of osteoblasts and precursors in Orai1−/− and control mice showed a significant decrease in alkaline phosphatase-expressing osteoblasts. In vitro studies confirmed that inhibiting Orai1 activity impaired differentiation and function of human osteoblasts, supporting a critical function for Orai1 in osteoblasts, in addition to its role as a regulator of osteoclast formation.
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影响因子：
20.3
作者：
Braun, Attila;Varga-Szabo, David;Nieswandt, Bernhard
通讯作者：
Nieswandt, Bernhard
影响因子：
4.8
作者：
Kim, Min Seuk;Yang, Yu-Mi;Shin, Dong Min
通讯作者：
Shin, Dong Min
影响因子：
3.5
作者：
Ellman, Michael B.;An, Howard S.;Im, Hee-Jeong
通讯作者：
Im, Hee-Jeong
影响因子：
64.8
作者：
Feske, S;Gwack, Y;Rao, A
通讯作者：
Rao, A
DOI：
10.1056/nejmoa0900082
发表时间：
2009-05-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Picard C;McCarl CA;Papolos A;Khalil S;Lüthy K;Hivroz C;LeDeist F;Rieux-Laucat F;Rechavi G;Rao A;Fischer A;Feske S
通讯作者：
Feske S