Extracellular matrix stiffness dictates Wnt expression through integrin pathway

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/beta-catenin pathway in both bone marrow mesenchymal stem cells and primary chondrocytes. The activation of beta-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 beta-catenin then bound to the wnt1 promoter region to up-regulate the gene transcription, thus constituting a positive feedback of the Wnt/beta-catenin pathway. With the amplifying effect of positive feedback, this integrin-activated beta-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.