Mechanosensitive miR-100 coordinates TGFβ and Wnt signaling in osteocytes during fluid shear stress

摘要

Organism scale mechanical forces elicit cellular scale changes through coordinated regulation of multiple signaling pathways. The mechanisms by which cells integrate signaling to generate a unified biological response remains a major question in mechanobiology. For example, the mechanosensitive response of bone and other tissuesrequires coordinated signaling by the transforming growth factor beta (TGFβ) and Wnt pathways through mechanisms that are not welldefined. Here we report a new microRNA-dependent mechanism that mediates mechanosensitive crosstalk between TGFβ and Wnt signaling in osteocytes exposed to fluid shear stress (FSS). From 60 mechanosensitive microRNA (miRs) identified by small-RNAseq, miR100 expression issuppressed by in vivo hindlimb loading in the murine tibia and by cellularscale FSS in OCY454 cells. Though FSS activates both TGFβ and Wnt signaling in osteocytes, only TGFβ represses miR100 expression. miR-100, in turn, antagonizes Wnt signaling by targeting and inhibiting expression of Frizzled receptors (FZD5/FZD8). Accordingly, miR-100 inhibition blunts FSS- and TGFβ-inducible Wnt signaling. Therefore, our results identify FSS-responsive miRNAs in osteocytes, including one that integrates the mechanosensitive function of two essential signaling pathways in the osteoanabolic response of bone to mechanical load.