Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-β-catenin
- Harvard School of Dental Medicine, United States
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China
- Nanfang Hospital, Southern Medical University, China
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
- Brigham and Women's Hospital, United States
- First Affiliated Hospital of Sun Yat-sen University, China
Abstract
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 β-catenin transcription factors by inducing their dephosphorylation as well as NFAT/YAP1/β-catenin complex formation. Yap1 and β-catenin activities were reduced in the Piezo1 and Piezo1/2 mutant bones and such defects were partially rescued by enhanced β-catenin activities.
Data availability
RNAseq source data for Figure. S3 has been deposited in GEO under the accession number GSE139121.All data generated or analysed during this study are included in the manuscript and supporting files.
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RNA seq of femur and humerus bone tissues from Prx1cre driven Piezo1/2 mutant pups at the age of P0NCBI Gene Expression Omnibus, GSE139121.
Article and author information
Author details
Funding
National Institute of Dental and Craniofacial Research (R01DE025866)
- Yingzi Yang
National Institute of Dental and Craniofacial Research (R01DE025866)
- Qian Cong
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070877)
- Yingzi Yang
National Cancer Institute (R01CA222571)
- Yuchen Liu
China Scholarship Council (201806380049)
- Taifeng Zhou
China Scholarship Council (201806210436)
- Jiachen Lin
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070877)
- Prem S Yadav
National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Yi Fan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the NIH. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#IS00000121-3) of the Harvard Medical School. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Harvard Medical School.
Copyright
© 2020, Zhou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-β-catenin
eLife 9:e52779.
https://doi.org/10.7554/eLife.52779
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