Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain.
Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain.
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缺乏 Cx43 胞质 C 端结构域的小鼠皮质骨松质骨结构缺陷和对 PTH 的异常反应。
DOI：
10.1016/j.bone.2015.09.011
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发表时间：
2015
期刊：
影响因子：
4.1
通讯作者：
Plotkin,LilianI
中科院分区：
文献类型：
--
作者：
Pacheco-Costa,Rafael;Davis,HannahM;Sorenson,Chad;Hon,MaryC;Hassan,Iraj;Reginato,RejaneD;Allen,MatthewR;Bellido,Teresita;Plotkin,LilianI
连接蛋白43（Cx43）形成间隙连接通道和半通道，其允许骨细胞、成骨细胞和破骨细胞之间的通信。Cx43羧基末端（CT）结构域通过作为结构蛋白和信号蛋白的支架来调节通道开放和细胞内信号传导。为了确定Cx43 CT结构域在骨中的作用，研究了其中全长Cx43的一个等位基因被缺乏CT结构域的突变体（Cx43ΔCT/fl）替换的小鼠。Cx43ΔCT/fl小鼠表现出比Cx43 fl/fl对照组更低的松质骨体积，但更高的皮质厚度，表明CT域参与正常松质骨获得，但反对皮质骨获得。此外，Cx43Δ CT能够发挥全长骨细胞Cx43对皮质骨几何形状和力学性能的功能，表明CT以外的结构域负责皮质骨中Cx43的功能。此外，甲状旁腺激素（PTH）未能增加Cx43Δ CT小鼠皮质骨（有或无骨细胞全长Cx43）中皮质骨的内皮质骨形成或失效能量，这是一种表明抗骨折性的机械特性。另一方面，在所有小鼠模型中，无论是否表达全长或Cx43Δ CT，激素均增加了骨量和骨形成标志物。我们的结论是，Cx43 CT域参与适当的骨收购，和Cx43在骨细胞中的表达是不稳定的一些，但不是所有的PTH合成代谢的行动。
Connexin 43 (Cx43) forms gap junction channels and hemichannels that allow the communication among osteocytes, osteoblasts, and osteoclasts. Cx43 carboxy-terminal (CT) domain regulates channel opening and intracellular signaling by acting as a scaffold for structural and signaling proteins. To determine the role of Cx43 CT domain in bone, mice in which one allele of full length Cx43 was replaced by a mutant lacking the CT domain (Cx43ΔCT/fl) were studied. Cx43ΔCT/flmice exhibit lower cancellous bone volume but higher cortical thickness than Cx43fl/flcontrols, indicating that the CT domain is involved in normal cancellous bone gain but opposes cortical bone acquisition. Further, Cx43ΔCTis able to exert the functions of full length osteocytic Cx43 on cortical bone geometry and mechanical properties, demonstrating that domains other than the CT are responsible for Cx43 function in cortical bone. In addition, parathyroid hormone (PTH) failed to increase endocortical bone formation or energy to failure, a mechanical property that indicates resistance to fracture, in cortical bone in Cx43ΔCTmice with or without osteocytic full length Cx43. On the other hand, bone mass and bone formation markers were increased by the hormone in all mouse models, regardless of whether full length or Cx43ΔCTwere or not expressed. We conclude that Cx43 CT domain is involved in proper bone acquisition; and that Cx43 expression in osteocytes is dispensable for some but not all PTH anabolic actions.