Role of pannexin 1 channels in load-induced skeletal response.
Role of pannexin 1 channels in load-induced skeletal response.
复制标题
pannexin 1 通道在负荷诱导的骨骼反应中的作用。
DOI：
10.1111/nyas.13914
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发表时间：
2019
影响因子：
5.2
通讯作者：
Thi,MiaM
中科院分区：
文献类型：
--
作者：
Seref-Ferlengez,Zeynep;Urban-Maldonado,Marcia;Sun,HuiB;Schaffler,MitchellB;Suadicani,SylviaO;Thi,MiaM
pannexin 1 （Panx1）通道是一种机械敏感通道，可与P2X7受体（P2X7R）相互作用，形成一种功能复合物，该复合物已在体外证明在骨细胞机械信号传导中起重要作用。虽然P2X7R参与骨骼对机械载荷的反应已被证实，但Panx1的作用及其与P2X7R的相互作用仍有待确定。在这项研究中，我们使用globalPanx1 - / -小鼠模型和体内力学加载来证明Panx1通道在负载诱导的骨骼反应中起重要作用。我们发现，Panx1的缺失不仅会破坏P2X7R - Panx1信号复合物，还会改变负荷诱导的P2X7R表达调控。此外，缺乏Panx1完全消除了负荷诱导的骨膜骨形成。与野生型相比，负荷诱导的β - catenin和sclerostin表达在panx1−/−中失调。这一发现表明Panx1缺乏通过降低β - catenin来破坏Wnt/β - catenin信号，同时通过增加负荷诱导的硬化蛋白表达来促进骨形成的抑制。这项研究证明了一种依赖Panx1的机械敏感机制的存在，该机制不仅可以调节ATP信号传导，还可以协调Wnt/β - catenin信号传导，这对于骨骼对机械负荷的适当反应至关重要。
The pannexin 1 (Panx1) channel is a mechanosensitive channel that interacts with P2X7 receptors (P2X7R) to form a functional complex that has been shownin vitroto play an essential role in osteocyte mechanosignaling. While the participation of P2X7R in skeletal responses to mechanical loading has been demonstrated, the role of Panx1 and its interplay with P2X7R still remain to be determined. In this study, we use a globalPanx1−/−mouse model andin vivomechanical loading to demonstrate that Panx1 channels play an essential role in load‐induced skeletal responses. We found that absence of Panx1 not only disrupts the P2X7R–Panx1 signaling complex, but also alters load‐induced regulation of P2X7R expression. Moreover, lack of Panx1 completely abolished load‐induced periosteal bone formation. Load‐induced regulation of β‐catenin and sclerostin expression was dysregulated inPanx1−/−, compared to wild‐type, bone. This finding suggests that Panx1 deficiency disrupts Wnt/β‐catenin signaling by lowering β‐catenin while favoring inhibition of bone formation by increasing load‐induced sclerostin expression. This study demonstrates the existence of a Panx1‐dependent mechanosensitive mechanism that not only modulates ATP signaling but also coordinates Wnt/β‐catenin signaling that is essential for proper skeletal response to mechanical loading.