Journal Article

Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-ß-catenin

Yadav, Prem S, Huang, Dongsheng, Gao, Bo, Zhang, Xiaolei, Zhou, Shuanhu, Wu, Nan, Lin, Jiachen, Zhou, Taifeng, Fan, Yi, Feng, Shuhao, Su, Peiqiang, Liu, Yuchen, Zhao, Liang, Cong, Qian, Yang, Yingzi, Zhou, Yaxing

2020

Overview

Mechanical forces are fundamental regulators of cell behaviors. However, molecular regulation of mechanotransduction remain poorly understood. Here, we identified the mechanosensitive channels Piezo1 and Piezo2 as key force sensors required for bone development and osteoblast differentiation. Loss of Piezo1, or more severely Piezo1/2, in mesenchymal or osteoblast progenitor cells, led to multiple spontaneous bone fractures in newborn mice due to inhibition of osteoblast differentiation and increased bone resorption. In addition, loss of Piezo1/2 rendered resistant to further bone loss caused by unloading in both bone development and homeostasis. Mechanistically, Piezo1/2 relayed fluid shear stress and extracellular matrix stiffness signals to activate Ca2+ influx to stimulate Calcineurin, which promotes concerted activation of NFATc1, YAP1 and ß-catenin transcription factors by inducing their dephosphorylation as well as NFAT/YAP1/ß-catenin complex formation. Yap1 and ß-catenin activities were reduced in the Piezo1 and Piezo1/2 mutant bones and such defects were partially rescued by enhanced ß-catenin activities.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Animals / beta Catenin - genetics / beta Catenin - metabolism / bone / Bone Development - genetics / Bone Development - physiology / Bone growth / Bone loss / Bone Marrow Cells / Bone resorption / Bones / Calcineurin / Calcium influx / Calcium signalling / Catenin / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Dephosphorylation / Developmental Biology / Extracellular matrix / Extremities - embryology / Fluid flow / Fractures / Gene Expression Regulation, Developmental - physiology / hippo signaling / Homeostasis / Hybridization / Ion Channels - genetics / Ion Channels - metabolism / Mechanical stimuli / Mechanosensitive channels / Mechanotransduction / Mechanotransduction, Cellular - physiology / Mesenchyme / Mice / Mice, Knockout / NF-AT protein / NFATC Transcription Factors - genetics / NFATC Transcription Factors - metabolism / osteoblast / Osteoblastogenesis / Osteogenesis / Osteoporosis / Osteoprogenitor cells / piezo1/2 / Progenitor cells / Protein expression / Proteins / Signal transduction / Stem cells / Stromal Cells - metabolism / Tendons / Tissue Culture Techniques / Transcription factors / Unloading / wnt signaling / Yes-associated protein