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Title: Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways

Abstract

TNF-α is known to induce osteoblasts apoptosis, whereas mechanical stimulation has been shown to enhance osteoblast survival. In the present study, we found that mechanical stimulation in the form of fluid shear stress (FSS) suppresses TNF-α induced apoptosis in MC3T3-E1 cells. Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family that has been implicated in cell survival. We also demonstrated that FSS imposed by flow chamber in vitro leads to a markedly activation of ERK5, which was shown to be protective against TNF-α-induced apoptosis, whereas the transfection of siRNA against ERK5 (ERK5-siRNA) reversed the FSS-medicated anti-apoptotic effects. An initial FSS-mediated activation of ERK5 that phosphorylates AKT to increase its activity, and a following forkhead box O 3a (FoxO3a) was phosphorylated by activated AKT. Phosphorylated FoxO3a is sequestered in the cytoplasm, and prevents it from translocating to nucleus where it can increase the expression of FasL and Bim. The inhibition of AKT-FoxO3a signalings by a PI3K (PI3-kinase)/AKT inhibitor (LY294002) or the transfection of ERK5-siRNA led to the nuclear translocation of non-phosphorylated FoxO3a, and increased the protein expression of FasL and Bim. In addition, the activation of caspase-3 by TNF-α was significantly inhibited by aforementioned FSS-medicatedmore » mechanisms. In brief, the activation of ERK5-AKT-FoxO3a signaling pathways by FSS resulted in a decreased expression of FasL and Bim and an inhibition of caspase-3 activation, which exerts a protective effect that prevents osteoblasts from apoptosis. - Highlights: • Fluid shear stress inhibits osteoblast apoptosis induced by TNF-α. • Inhibition of ERK5 activity by transfection of ERK5 siRNA blocks FSS-mediated anti-apoptotic effect in osteoblast. • Activated ERK5-AKT-FoxO3a-Bim/FasL signaling pathways by FSS is required to protect osteoblast from apoptosis.« less

Authors:
; ; ; ; ; ; ; ; ;  [1];  [2];  [1];  [2]
  1. The Second Hospital of Lanzhou University, #82 Cuiyingmen, Lanzhou, 730000 Gansu (China)
  2. (China)
Publication Date:
OSTI Identifier:
22648571
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 343; Journal Issue: 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CELL NUCLEI; CELL PROLIFERATION; CONNECTIVE TISSUE CELLS; CYTOPLASM; FLUIDS; IN VITRO; INHIBITION; MITOGENS; PHOSPHOTRANSFERASES; SHEAR; SIGNALS; STIMULATION; TRANSLOCATION

Citation Formats

Bin, Geng, Bo, Zhang, Jing, Wang, Jin, Jiang, Xiaoyi, Tan, Cong, Chen, Liping, An, Jinglin, Ma, Cuifang, Wang, Yonggang, Chen, Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu, Yayi, Xia, E-mail: xiayayildey@163.com, and Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu. Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways. United States: N. p., 2016. Web. doi:10.1016/J.YEXCR.2016.03.014.
Bin, Geng, Bo, Zhang, Jing, Wang, Jin, Jiang, Xiaoyi, Tan, Cong, Chen, Liping, An, Jinglin, Ma, Cuifang, Wang, Yonggang, Chen, Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu, Yayi, Xia, E-mail: xiayayildey@163.com, & Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu. Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways. United States. doi:10.1016/J.YEXCR.2016.03.014.
Bin, Geng, Bo, Zhang, Jing, Wang, Jin, Jiang, Xiaoyi, Tan, Cong, Chen, Liping, An, Jinglin, Ma, Cuifang, Wang, Yonggang, Chen, Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu, Yayi, Xia, E-mail: xiayayildey@163.com, and Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu. Sun . "Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways". United States. doi:10.1016/J.YEXCR.2016.03.014.
@article{osti_22648571,
title = {Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways},
author = {Bin, Geng and Bo, Zhang and Jing, Wang and Jin, Jiang and Xiaoyi, Tan and Cong, Chen and Liping, An and Jinglin, Ma and Cuifang, Wang and Yonggang, Chen and Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu and Yayi, Xia, E-mail: xiayayildey@163.com and Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu},
abstractNote = {TNF-α is known to induce osteoblasts apoptosis, whereas mechanical stimulation has been shown to enhance osteoblast survival. In the present study, we found that mechanical stimulation in the form of fluid shear stress (FSS) suppresses TNF-α induced apoptosis in MC3T3-E1 cells. Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family that has been implicated in cell survival. We also demonstrated that FSS imposed by flow chamber in vitro leads to a markedly activation of ERK5, which was shown to be protective against TNF-α-induced apoptosis, whereas the transfection of siRNA against ERK5 (ERK5-siRNA) reversed the FSS-medicated anti-apoptotic effects. An initial FSS-mediated activation of ERK5 that phosphorylates AKT to increase its activity, and a following forkhead box O 3a (FoxO3a) was phosphorylated by activated AKT. Phosphorylated FoxO3a is sequestered in the cytoplasm, and prevents it from translocating to nucleus where it can increase the expression of FasL and Bim. The inhibition of AKT-FoxO3a signalings by a PI3K (PI3-kinase)/AKT inhibitor (LY294002) or the transfection of ERK5-siRNA led to the nuclear translocation of non-phosphorylated FoxO3a, and increased the protein expression of FasL and Bim. In addition, the activation of caspase-3 by TNF-α was significantly inhibited by aforementioned FSS-medicated mechanisms. In brief, the activation of ERK5-AKT-FoxO3a signaling pathways by FSS resulted in a decreased expression of FasL and Bim and an inhibition of caspase-3 activation, which exerts a protective effect that prevents osteoblasts from apoptosis. - Highlights: • Fluid shear stress inhibits osteoblast apoptosis induced by TNF-α. • Inhibition of ERK5 activity by transfection of ERK5 siRNA blocks FSS-mediated anti-apoptotic effect in osteoblast. • Activated ERK5-AKT-FoxO3a-Bim/FasL signaling pathways by FSS is required to protect osteoblast from apoptosis.},
doi = {10.1016/J.YEXCR.2016.03.014},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 2,
volume = 343,
place = {United States},
year = {2016},
month = {5}
}