Differential Impact of Fluid Shear Stress and YAP/TAZ on BMP/TGF‐β Induced Osteogenic Target Genes

Bone is a remarkable dynamic structure, which integrates mechanical and biochemical signaling inputs. Interstitial fluid in the intramedullary space transmits signals derived from compression‐induced fluid shear stress (FSS) to stimulate osteoblasts for bone formation. Using a flow system and human osteoblasts, this study demonstrates how BMP/TGF‐β signaling integrates stimuli derived from FSS and YAP/TAZ and confirms these findings by transcriptome analyses. Here, FSS positively affects the phosphorylation of both SMAD1/5 and SMAD2/3, the respective BMP‐ and TGFβ‐R‐SMADs. Increase in phosphorylated SMAD1/5 levels affects distinct target genes, which are susceptible to low levels of phosphorylated SMADs (such as ID1–3) or dependent on high levels of phosphorylated SMAD1/5 (NOG, noggin). Thus, FSS lowers the threshold for genes dependent on high levels of phosphorylated SMAD1/5 when less BMP is available. While the impact of FSS on direct BMP target genes is independent of YAP/TAZ, FSS acts cooperatively with YAP/TAZ on TGF‐β target genes, which are shared by both pathways (such as CTGF). As mechanical stimuli are key in bone regeneration, their crosstalk to biochemical signaling pathways such as BMP and TGF‐β and YAP/TAZ acts on different levels, which allows now to think about new and more specified intervention strategies for age‐related bone loss. It is demonstrated that osteogenic differentiation is promoted by fluid shear stress and mediated via YAP/TAZ and SMAD pathways. With a whole‐genome approach, it is shown that low‐affinity SMAD target genes are dependent on YAP/TAZ while high‐affinity targets are independent. Therapies to treat bone loss will benefit from considering this new molecular intersection of fluid flow with BMP/TGF‐β/SMAD and YAP/TAZ signaling.