Nmp4/CIZ inhibits mechanically induced beta-catenin signaling activity in osteoblasts.
Nmp4/CIZ inhibits mechanically induced beta-catenin signaling activity in osteoblasts.
复制标题
DOI：
10.1002/jcp.22057
复制
发表时间：
2010-05
影响因子：
5.6
通讯作者：
Pavalko, Fredrick M.
中科院分区：
文献类型：
--
作者：
Yang, Zhouqi;Bidwell, Joseph P.;Young, Suzanne R.;Gerard-O'Riley, Rita;Wang, Haifang;Pavalko, Fredrick M.
细胞机械转导，将机械信号转化为细胞内的生化反应的过程，是骨骼健康的一个重要方面。虽然机械负荷对骨的影响是公认的，阐明骨细胞处理机械信号的特定分子途径代表了一个挑战和机会，以确定治疗策略，以打击骨丢失。在本研究中，我们首次研究了成骨细胞中的核质穿梭转录因子核基质蛋白-4/cas相互作用锌指蛋白（Nmp 4/CIZ）和β-连环蛋白信号对生理性机械刺激（振荡流体剪切应力，OFSS）的反应之间的关系。使用来自Nmp 4缺陷型和野生型小鼠的颅骨来源的成骨细胞，我们发现当Nmp 4/CIZ不存在时，由OFSS诱导的成骨细胞中β-连环蛋白向细胞核的正常易位增强。此外，我们发现OFSS诱导的机械转导的其他方面通常与β-catenin信号通路相关，包括ERK，Akt和GSK 3 β活性，以及β-catenin响应蛋白cyclin D1的表达也在缺乏Nmp 4/CIZ的细胞中增强。最后，我们发现，在Nmp 4/CIZ的情况下，OFSS诱导的细胞骨架重组和成骨细胞与细胞外基质之间的粘着斑的形成是定性增强的，这表明Nmp 4/CIZ可能会降低骨细胞对机械刺激的敏感性。总之，这些结果为Nmp 4/CIZ在骨细胞对OFSS诱导的机械刺激的反应中起抑制作用的概念提供了实验支持。
Cellular mechanotransduction, the process of converting mechanical signals into biochemical responses within cells, is a critical aspect of bone health. While the effects of mechanical loading on bone are well recognized, elucidating the specific molecular pathways involved in the processing of mechanical signals by bone cells represents a challenge and an opportunity to identify therapeutic strategies to combat bone loss. In this study we have for the first time examined the relationship between the nucleocytoplasmic shuttling transcription factor nuclear matrix protein-4/cas interacting zinc finger protein (Nmp4/CIZ) and β-catenin signaling in response to a physiologic mechanical stimulation (oscillatory fluid shear stress, OFSS) in osteoblasts. Using calvaria-derived osteoblasts from Nmp4-deficient and wild-type mice, we found that the normal translocation of β-catenin to the nucleus in osteoblasts that is induced by OFSS is enhanced when Nmp4/CIZ is absent. Furthermore, we found that other aspects of OFSS-induced mechanotransduction generally associated with the β-catenin signaling pathway, including ERK, Akt and GSK3β activity, as well as expression of the β-catenin-responsive protein cyclin D1 are also enhanced in cells lacking Nmp4/CIZ. Finally, we found that in the absence of Nmp4/CIZ, OFSS-induced cytoskeletal reorganization and the formation of focal adhesions between osteoblasts and the extracellular substrate is qualitatively enhanced, suggesting that Nmp4/CIZ may reduce the sensitivity of bone cells to mechanical stimuli. Together these results provide experimental support for the concept that Nmp4/CIZ plays an inhibitory role in the response of bone cells to mechanical stimulation induced by OFSS.
登录
查看更多内容
影响因子：
4
作者：
Santos, A.;Bakker, A. D.;Klein-Nulend, J.
通讯作者：
Klein-Nulend, J.
影响因子：
5.6
作者：
Pavalko, FM;Gerard, RL;Norvell, SM
通讯作者：
Norvell, SM
影响因子：
4.2
作者：
Norvell, SM;Alvarez, M;Pavalko, FM
通讯作者：
Pavalko, FM
影响因子：
4.8
作者：
Ogita, Mami;Rached, Marie Therese;Kousteni, Stavroula
通讯作者：
Kousteni, Stavroula
影响因子：
4.8
作者：
Guo, Wen;Flanagan, John;Bhasin, Shalender
通讯作者：
Bhasin, Shalender