Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function
Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function
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DOI：
10.1210/en.2011-1814
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发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
Williams, Graham R.
中科院分区：
文献类型：
--
作者：
Bassett, J. H. Duncan;Logan, John G.;Williams, Graham R.
钙调神经磷酸酶-活化T细胞核因子信号通路控制破骨细胞和成骨细胞的分化和功能，钙调神经磷酸酶调节因子2（Regulator of calcineurin-2，Rcan 2）是该通路的生理抑制剂。Rcan 2的表达受T-3的调节，T-3在骨骼发育和骨转换中也起着重要作用。为了研究Rcan 2在骨发育和维持中的作用，我们表征了Rcan 2（-/-）小鼠，并测定了其在T-3受体（TR）敲除和甲状腺操作小鼠中的骨骼表达。Rcan 2（-/-）小鼠具有正常的线性生长，但显示膜内骨化延迟，皮质骨形成受损，发育期间骨矿物质积累减少以及成年骨矿化增加。这些异常是由成骨细胞功能的孤立缺陷引起的，与缺乏2型脱碘酶甲状腺激素激活酶或TR β（骨中主要的TR亚型）显性阴性突变的小鼠的骨骼表型相似。Rcan 2 mRNA在原代破骨细胞和成骨细胞中表达，其在骨中的表达在TR α和TR β敲除和甲状腺操作的小鼠中受到差异调节。然而，在原代成骨细胞培养中，T-3处理不影响Rcan 2 mRNA表达或活化T细胞核因子c1表达和磷酸化。总之，这些研究确定Rcan 2调节成骨细胞功能，并且其在骨中的表达受体内甲状腺状态调节。（内分泌学153：3537-3548，2012）
Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T-3, which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2(-/-) mice and determined its skeletal expression in T-3 receptor (TR) knockout and thyroid-manipulated mice. Rcan2(-/-) mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TR beta, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TR alpha and TR beta knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T-3 treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo. (Endocrinology 153: 3537-3548, 2012)