title: Extracellular signal-regulated kinase1/2 activated by fluid shear stress promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells through novel signaling pathways.
abstract: It is a classical signaling pathway that the activation of extracellular signal-regulated kinase1/2 (ERK1/2) results in the phosphorylation of runt-related transcription factor 2 (Runx2) and thereby initiates the transcription of osteogenic genes. Recently, it is found that the activation of ERK1/2 resulted from fluid shear stress (FSS) also increased the expression of Runx2 and β1 integrins, and finally enhanced osteogenic differentiation. However, it has been remained largely unknown how ERK1/2 regulates the expression of Runx2 and β1 integrins. We use the perfusion culture system to produce FSS exerting on human bone marrow-derived mesenchymal stem cells (hMSCs) and thus activate ERK1/2. Our study demonstrated that FSS-activated ERK1/2 mediated the expression of osteogenic genes via two novel signaling pathways except for the classical signaling pathway: feedback up-regulation of β1 integrins expression via activating nuclear factor kappa B (NF-κB), and activation of bone morphogenesis proteins (BMPs)/mothers against decapentaplegic (Smad) pathway via activating NF-κB and thereby regulating Runx2 expression. These signaling pathways combined with the classical signaling pathway, with ERK1/2 as a hub node molecule, form a molecular signaling cross-talking network to induce the osteogenic differentiation of hMSCs. The understanding on the mechanism of FSS inducing the osteogenic differentiation of hMSCs will not only be helpful to develop the bone tissue engineering but also provide new targets for drug discovery for treatment of osteoporosis and other related bone-wasting diseases.
authors.affiliation: Institute of Cell Biology, College of Life Sciences, Zhejiang University, Zijingang Campus, Hangzhou 310058, PR China.
authors.forename: Liyue
authors.initials: L
authors.lastname: Liu
authors.forename: Lan
authors.initials: L
authors.lastname: Shao
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Zong
authors.forename: Jianhu
authors.initials: J
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zheng
authors.forename: Xiangming
authors.initials: X
authors.lastname: Tong
authors.forename: Changyou
authors.initials: C
authors.lastname: Gao
authors.forename: Jinfu
authors.initials: J
authors.lastname: Wang
mesh_terms: D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010012:Osteogenesis; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D013314:Stress, Mechanical; D023822:Tissue Engineering; D015854:Up-Regulation
chemical_list: D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D019012:Integrin beta1; D016328:NF-kappa B; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3