Crosstalk between Caveolin-1/Extracellular Signal-regulated Kinase (ERK) and β-Catenin Survival Pathways in Osteocyte Mechanotransduction
Crosstalk between Caveolin-1/Extracellular Signal-regulated Kinase (ERK) and β-Catenin Survival Pathways in Osteocyte Mechanotransduction
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DOI：
10.1074/jbc.m112.437921
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发表时间：
2013-03-22
影响因子：
4.8
通讯作者：
Bellido, Teresita
中科院分区：
文献类型：
--
作者：
Gortazar, Arancha R.;Martin-Millan, Marta;Bellido, Teresita
骨细胞活力是骨强度的关键决定因素，并通过机械刺激和Wnt信号通路的激活来促进。早期的研究表明，这两种刺激通过激活ERK来促进骨细胞的存活。在这里，我们表明，有小窝蛋白-1/ERK和Wnt/β-连环蛋白信号通路之间的相互作用，在机械信号转导成骨细胞的生存。因此，Wnt拮抗剂Dkk 1和β-连环蛋白降解刺激剂Axin 2消除了机械刺激诱导的ERK核转位和抗凋亡。相反地，通过ERK的药理学抑制或沉默小窝蛋白-1来消除由机械刺激诱导的GSK 3 β磷酸化和β-连环蛋白积累。相反，经典的Wnt信号传导抑制剂显性负性T细胞因子不改变ERK核转位或机械刺激诱导的存活。这些发现表明，β-连环蛋白积累是骨细胞中机械转导机制的重要组成部分，尽管不需要β-连环蛋白/T细胞因子介导的转录。ERK激活β-连环蛋白和ERK激活β-连环蛋白积累的同时需求表明，在导致骨细胞存活的机械转导中，小窝蛋白-1/ERK和Wnt/β-连环蛋白通路之间存在双向串扰。
Osteocyte viability is a critical determinant of bone strength and is promoted by both mechanical stimulation and activation of the Wnt signaling pathway. Earlier studies demonstrated that both stimuli promote survival of osteocytes by activating the ERKs. Here, we show that there is interaction between the caveolin-1/ERK and Wnt/beta-catenin signaling pathways in the transduction of mechanical cues into osteocyte survival. Thus, ERK nuclear translocation and anti-apoptosis induced by mechanical stimulation are abolished by the Wnt antagonist Dkk1 and the beta-catenin degradation stimulator Axin2. Conversely, GSK3 beta phosphorylation and beta-catenin accumulation induced by mechanical stimulation are abolished by either pharmacologic inhibition of ERKs or silencing caveolin-1. In contrast, the canonical Wnt signaling inhibitor dominant-negative T cell factor does not alter ERK nuclear translocation or survival induced by mechanical stimulation. These findings demonstrate that beta-catenin accumulation is an essential component of the mechanotransduction machinery in osteocytes, albeit beta-catenin/T cell factor-mediated transcription is not required. The simultaneous requirement of beta-catenin for ERK activation and of ERK activation for beta-catenin accumulation suggests a bidirectional crosstalk between the caveolin-1/ERK and Wnt/beta-catenin pathways in mechanotransduction leading to osteocyte survival.