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.
Highlights
In vivo chondrocytes were embedded in pericellular matrix (PCM) of which the mechanical property is crucial in the environment of the chondrocyte[16]
BIO, an inhibitor of glycogen synthase kinase 3β (GSK3β), significantly diminished the influence of ECM stiffness on Wnt[1] expression, as well as β -catenin accumulation (Fig. 5h). These results indicate that the β -catenin/Wnt pathway is activated by stiff ECM via inhibition of GSK3β by integrin-dependent downstream signals
We explored the effect of the integrin-activated β -catenin/Wnt pathway on the functional responses of primary chondrocytes and bone marrow mesenchymal stem cells (BMMSCs) to ECM stiffness
Summary
The stiffness of the ColII or matrigel-coated substrates up-regulated the levels of Wnt[1] and β -catenin in chondrocytes, as ColI (Fig. 1j,k). A more specific inhibition by β -catenin siRNA significantly down-regulated the Wnt[1] expression and diminished the difference of Wnt[1] levels in cells on soft and stiff substrate. The inhibition of β 1 integrin by a functional blocking antibody (clone HMβ 1-1) significantly diminished the influence of ECM stiffness on the levels of phosphorylated GSK3β , β -catenin and Wnt[1] (Fig. 4a–c).
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