Mechanosensitive Mir-100 Coordinates Tgf Beta And Wnt Signaling In Osteocytes During Fluid Shear Stress

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 tissues requires coordinated signaling by the transforming growth factor beta (TGF beta) and Wnt pathways through mechanisms that are not well-defined. Isere we report a new microRNA-dependent mechanism that mediates mechanosensitive crosstalk between TGFI3 and Wnt signaling in osteocytes exposed to fluid shear stress (FSS). From 60 mechanosensitive microRNA (miRs) identified by small-RNAseq, miR100 expression is suppressed by in vivo hind limb loading in the murine tibia and by cellular scale FSS in OCY454 cells. Though FSS activates both TGF beta and Wnt signaling in osteocytes, only TGIT 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 TGF beta-inducible Wnt signaling. Therefore, our results identify FSS-responsive mi RNAs in osteocytes, including one that integrates the mechanosensitive function of two essential signaling pathways in the osteoanabolic response of bone to mechanical load.