Fluid shear stress induces β-catenin signaling in osteoblasts
Fluid shear stress induces β-catenin signaling in osteoblasts
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DOI：
10.1007/s00223-004-0213-y
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发表时间：
2004-11-01
影响因子：
4.2
通讯作者：
Pavalko, FM
中科院分区：
文献类型：
--
作者：
Norvell, SM;Alvarez, M;Pavalko, FM
β-连环蛋白在细胞中起双重作用：一个在细胞-细胞连接处，另一个在细胞核中与TCF（T细胞因子）一起调节基因转录。最近，β-连环蛋白在成骨细胞分化和基因表达中的作用已开始阐明。在此，我们研究了流体剪切应力（FSS）对β-连环蛋白信号转导的影响。FSS是成骨细胞的一种特征良好的合成代谢刺激;然而，这种刺激作用的分子机制在很大程度上仍然未知。我们发现，1小时的层流FSS（10达因/cm（2））诱导β-连环蛋白易位到细胞核，并激活TCF报告基因。对可能调节β-连环蛋白信号传导活性的上游信号的分析揭示了增加β-连环蛋白信号传导的两种潜在机制。首先，FSS诱导了糖原合成酶激酶3 β（GSK-3 β）和Akt磷酸化的短暂但显著的增加。第二，FSS降低了与N-钙粘蛋白相关的β-连环蛋白的水平，表明在遭受FSS的成骨细胞中，钙粘蛋白对β-连环蛋白的螯合作用较少。成骨细胞中β-连环蛋白信号调节的潜在基因的功能分析揭示了两个新的观察结果。首先，从成骨细胞中纯化的内源性核β-连环蛋白与环加氧酶-2启动子中的TCF结合元件形成复合物，其次，组成型活性β-连环蛋白分子的过表达或GSK-3 β活性的抑制增加了基础环加氧酶-2水平。总之，这些数据首次证明，FSS调节GSK-3 β和β-连环蛋白的活性，并且这些信号分子调节成骨细胞中环氧合酶-2的表达。
beta-Catenin plays a dual role in cells: one at cell-cell junctions and one regulating gene transcription together with TCF (T-cell Factor) in the nucleus. Recently, a role for beta-catenin in osteoblast differentiation and gene expression has begun to be elucidated. Herein we investigated the effects of fluid shear stress (FSS) on beta-catenin signaling. FSS is a well-characterized anabolic stimulus for osteoblasts; however, the molecular mechanisms for the effects of this stimulation remain largely unknown. We found that I hour of laminar FSS (10 dynes/cm(2)) induced translocation of beta-catenin to the nucleus and activated a TCF-reporter gene. Analysis of upstream signals that may regulate beta-catenin signaling activity revealed two potential mechanisms for increased P-catenin signaling. First, FSS induced a transient, but significant, increase in the phosphorylation of both glycogen synthase kinase 3beta (GSK-3beta) and Akt. Second, FSS reduced the levels of beta-catenin associated with N-cadherin, suggesting that less sequestration of beta-catenin by cadherins occurs in osteoblasts subjected to FSS. Functional analysts of potential genes regulated by beta-catenin signaling in osteoblasts revealed two novel observations. First, endogenous, nuclear beta-catenin purified from osteoblasts formed a complex with a TCF -binding element in the cyclooxygenase-2 promoter, and, second, overexpression of either a constitutively active beta-catenin molecule or inhibition of GSK-3beta activity increased basal cyclooxygenase-2 levels. Together, these data demonstrate for the first time that FSS modulates the activity of both GSK-3beta and beta-catenin and that these signaling molecules regulate cyclooxygenase-2 expression in osteoblasts.