1. Developmental Biology
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Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-β-catenin

  1. Taifeng Zhou
  2. Bo Gao
  3. Yi Fan
  4. Yuchen Liu
  5. Shuhao Feng
  6. Qian Cong
  7. Xiaolei Zhang
  8. Yaxing Zhou
  9. Prem S Yadav
  10. Jiachen Lin
  11. Nan Wu
  12. Liang Zhao
  13. Dongsheng Huang
  14. Shuanhu Zhou
  15. Peiqiang Su  Is a corresponding author
  16. Yingzi Yang  Is a corresponding author
  1. Harvard School of Dental Medicine, United States
  2. Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China
  3. Nanfang Hospital, Southern Medical University, China
  4. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
  5. Brigham and Women's Hospital, United States
  6. First Affiliated Hospital of Sun Yat-sen University, China
Research Article
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Cite this article as: eLife 2020;9:e52779 doi: 10.7554/eLife.52779

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.

Article and author information

Author details

  1. Taifeng Zhou

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Bo Gao

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yi Fan

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuchen Liu

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shuhao Feng

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Qian Cong

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiaolei Zhang

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yaxing Zhou

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Prem S Yadav

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jiachen Lin

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Nan Wu

    Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9429-2889
  12. Liang Zhao

    Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Dongsheng Huang

    Department of Spine Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Shuanhu Zhou

    Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Peiqiang Su

    Department of Orthopaedic Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    For correspondence
    supq@mail.sysu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  16. Yingzi Yang

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    For correspondence
    yingzi_yang@hsdm.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3933-887X

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.

Reviewing Editor

  1. Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: October 16, 2019
  2. Accepted: March 17, 2020
  3. Accepted Manuscript published: March 18, 2020 (version 1)
  4. Version of Record published: April 1, 2020 (version 2)

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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