N-Cadherin Interacts with Axin and LRP5 To Negatively Regulate Wnt/β-Catenin Signaling, Osteoblast Function, and Bone Formation
N-Cadherin Interacts with Axin and LRP5 To Negatively Regulate Wnt/β-Catenin Signaling, Osteoblast Function, and Bone Formation
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DOI：
10.1128/mcb.00349-08
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发表时间：
2009-02-15
影响因子：
5.3
通讯作者：
Marie, Pierre J.
中科院分区：
文献类型：
--
作者：
Hay, Eric;Laplantine, Emmanuel;Marie, Pierre J.
Wnt信号在骨形成和骨量的调节中起着重要作用。在成骨细胞中调节经典Wnt信号传导的机制还不完全清楚。我们在这里展示了一种新的机制，通过这种机制，粘附分子N-钙粘蛋白与Wnt辅助受体LRP 5相互作用，并调节成骨细胞中的经典Wnt/β-连环蛋白信号传导。我们证明，N-钙粘蛋白，除了与β-连环蛋白在膜上，形成一个分子复合物与轴和LRP 5涉及LRP 5胞质尾域。成骨细胞中的N-钙粘蛋白过表达增加了N-钙粘蛋白-LRP 5的相互作用，导致响应Wnt 3a的β-连环蛋白降解增加和TCF/LEF转录改变。该机制导致在基础条件下和响应于Wnt 3a的成骨细胞基因表达和骨生成降低。与功能机制一致，沉默对照细胞中的N-钙粘蛋白表达增加TCF/LEF转录并增强对Wnt 3a的应答。使用N-cadherin转基因小鼠，我们发现，增加N-cadherin-LRP 5相互作用导致的N-钙粘蛋白在成骨细胞中的靶向过表达，导致β-连环蛋白泛素化增加，并导致细胞自主性成骨细胞功能缺陷，骨形成减少，骨量获得延迟。这些数据表明，以前未被识别的N-钙粘蛋白-轴蛋白-LRP 5相互作用负调控Wnt/β-连环蛋白信号传导，并在成骨细胞功能，骨形成和骨量的调节中至关重要。
Wnt signaling plays an important role in the regulation of bone formation and bone mass. The mechanisms that regulate canonical Wnt signaling in osteoblasts are not fully understood. We show here a novel mechanism by which the adhesion molecule N-cadherin interacts with the Wnt coreceptor LRP5 and regulates canonical Wnt/beta-catenin signaling in osteoblasts. We demonstrate that N-cadherin, besides associating with beta-catenin at the membrane, forms a molecular complex with axin and LRP5 involving the LRP5 cytoplasmic tail domain. N-cadherin overexpression in osteoblasts increases N-cadherin-LRP5 interaction, causing increased beta-catenin degradation and altered TCF/LEF transcription in response to Wnt3a. This mechanism results in decreased osteoblast gene expression and osteogenesis in basal conditions and in response to Wnt3a. Consistent with a functional mechanism, silencing N-cadherin expression in control cells increases TCF/LEF transcription and enhances the response to Wnt3a. Using N-cadherin transgenic mice, we show that increased N-cadherin-LRP5 interaction resulting from targeted overexpression of N-cadherin in osteoblasts causes increased beta-catenin ubiquitination and results in cell-autonomous defective osteoblast function, reduced bone formation, and delayed bone mass acquisition. These data indicate that a previously unrecognized N-cadherin-axin-LRP5 interaction negatively regulates Wnt/beta-catenin signaling and is critical in the regulation of osteoblast function, bone formation, and bone mass.