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β-连环蛋白/E-钙黏蛋白复合体形成的改变在 Saos-2 成骨细胞的机械转导过程中。

Alterations in β‑catenin/E‑cadherin complex formation during the mechanotransduction of Saos‑2 osteoblastic cells.

机构信息

State Key Laboratory of Military Stomatology, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

Department of Pathophysiology, School of Basic Medical Sciences, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

出版信息

Mol Med Rep. 2018 Aug;18(2):1495-1503. doi: 10.3892/mmr.2018.9146. Epub 2018 Jun 7.

Abstract

Mechanical load application promotes bone formation, while reduced load leads to bone loss. However, the underlying mechanisms that regulate new bone formation are not fully understood. Wnt/β‑catenin signaling has an important role in bone formation, bone growth and remodeling. The aim of the present study was to investigate whether mechanical stimuli regulated bone formation through the Wnt/β‑catenin signaling pathway. Saos‑2 osteoblastic cells were subjected to mechanical strain using a Flexcell strain loading system. The results demonstrated that 12% cyclical tensile stress significantly stimulated Saos‑2 cell proliferation, increased the activity of alkaline phosphatase and promoted the formation of mineralized nodules, as determined by MTT and p‑nitrophenyl phosphate assays and Alizarin Red S staining, respectively. Furthermore, western blot analysis demonstrated that, following mechanical strain, increased phosphorylation of glycogen synthase kinase‑3β and nuclear β‑catenin expression was observed in cells, compared with static control culture cells. Results of reporter gene and reverse transcription‑polymerase chain reaction assays also demonstrated that mechanical strain significantly increased T‑cell factor reporter gene activity and the mRNA expression of cyclooxygenase (COX)‑2, cyclin D1, c‑fos and c‑Jun in Saos‑2 cells. Co‑immunoprecipitation analysis revealed that elongation mechanical strain activated Wnt/β‑catenin signaling and reduced β‑catenin and E‑cadherin interaction in Saos‑2 cells. In conclusion, the results of the current study indicate that mechanical strain may have an important role in the proliferation and differentiation of osteoblasts. The disassociation of the β‑catenin/E‑cadherin complex in the osteoblast membrane under stretch loading and the subsequent translocation of β‑catenin into the nucleus may be an intrinsic mechanical signal transduction mechanism.

摘要

机械负荷的施加可促进骨形成,而减少负荷则会导致骨质流失。然而,调节新骨形成的潜在机制尚未完全阐明。Wnt/β-连环蛋白信号通路在骨形成、骨生长和重塑中具有重要作用。本研究旨在探讨机械刺激是否通过 Wnt/β-连环蛋白信号通路来调节骨形成。采用 Flexcell 应变加载系统对 Saos-2 成骨细胞施加机械应变。结果表明,12%周期性张应变显著刺激 Saos-2 细胞增殖,增加碱性磷酸酶活性,并通过 MTT 和对硝基苯磷酸酯测定法以及茜素红 S 染色分别促进矿化结节的形成。此外,Western blot 分析表明,与静态对照培养细胞相比,机械应变后细胞中糖原合成酶激酶-3β的磷酸化和核β-连环蛋白表达增加。报告基因和逆转录-聚合酶链反应检测结果还表明,机械应变显著增加了 T 细胞因子报告基因活性以及 Saos-2 细胞中环氧化酶(COX)-2、细胞周期蛋白 D1、c-fos 和 c-Jun 的 mRNA 表达。共免疫沉淀分析表明,伸长机械应变激活了 Wnt/β-连环蛋白信号通路,并降低了 Saos-2 细胞中β-连环蛋白和 E-钙黏蛋白的相互作用。综上所述,本研究结果表明,机械应变可能在成骨细胞的增殖和分化中具有重要作用。在拉伸加载下,成骨细胞膜中β-连环蛋白/E-钙黏蛋白复合物的解离以及随后β-连环蛋白向核内易位可能是一种内在的机械信号转导机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/581b/6072157/cb3e75753bc5/MMR-18-02-1495-g00.jpg

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