title: Extracellular matrix stiffness dictates Wnt expression through integrin pathway.
abstract: It is well established that extracellular matrix (ECM) stiffness plays a significant role in regulating the phenotypes and behaviors of many cell types. However, the mechanism underlying the sensing of mechanical cues and subsequent elasticity-triggered pathways remains largely unknown. We observed that stiff ECM significantly enhanced the expression level of several members of the Wnt/β-catenin pathway in both bone marrow mesenchymal stem cells and primary chondrocytes. The activation of β-catenin by stiff ECM is not dependent on Wnt signals but is elevated by the activation of integrin/ focal adhesion kinase (FAK) pathway. The accumulated β-catenin then bound to the wnt1 promoter region to up-regulate the gene transcription, thus constituting a positive feedback of the Wnt/β-catenin pathway. With the amplifying effect of positive feedback, this integrin-activated β-catenin/Wnt pathway plays significant roles in mediating the enhancement of Wnt signal on stiff ECM and contributes to the regulation of mesenchymal stem cell differentiation and primary chondrocyte phenotype maintenance. The present integrin-regulated Wnt1 expression and signaling contributes to the understanding of the molecular mechanisms underlying the regulation of cell behaviors by ECM elasticity.
authors: Institute of Biomechanics and Medical Engineering, School of Aerospace, Tsinghua University, Beijing 100084, P.R. China.
authors: Jing
authors: J
authors: Du
authors: Institute of Biomechanics and Medical Engineering, School of Aerospace, Tsinghua University, Beijing 100084, P.R. China.
authors: Yan
authors: Y
authors: Zu
authors: Institute of Biomechanics and Medical Engineering, School of Aerospace, Tsinghua University, Beijing 100084, P.R. China.
authors: Jing
authors: J
authors: Li
authors: Institute of Biomechanics and Medical Engineering, School of Aerospace, Tsinghua University, Beijing 100084, P.R. China.
authors: Shuyuan
authors: S
authors: Du
authors: School of Stomatology, Lanzhou University, 730000, P.R. China.
authors: Yipu
authors: Y
authors: Xu
authors: Department of Pharmacology, School of Medicine, Tsinghua University, Beijing 100084, P.R. China.
authors: Lang
authors: L
authors: Zhang
authors: Institute of Biomechanics and Medical Engineering, School of Aerospace, Tsinghua University, Beijing 100084, P.R. China.
authors: Li
authors: L
authors: Jiang
authors: Department of Pharmacology, School of Medicine, Tsinghua University, Beijing 100084, P.R. China.
authors: Zhao
authors: Z
authors: Wang
authors: Departments of Bioengineering and Medicine, and Institute of Engineering in Medicine, University of California at San Diego, La Jolla, CA 92093.
authors: Shu
authors: S
authors: Chien
authors: Institute of Biomechanics and Medical Engineering, School of Aerospace, Tsinghua University, Beijing 100084, P.R. China.
authors: Chun
authors: C
authors: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016023:Integrins; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin