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A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction

Author

Listed:
  • Tadatoshi Sato

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Shiv Verma

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Christian D. Castro Andrade

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Maureen Omeara

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Nia Campbell

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Jialiang S. Wang

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Murat Cetinbas

    (Department of Molecular Biology and Department of Pathology, Massachusetts General Hospital, Harvard Medical School)

  • Audrey Lang

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Brandon J. Ausk

    (University of Washington)

  • Daniel J. Brooks

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School
    Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Ruslan I. Sadreyev

    (Department of Molecular Biology and Department of Pathology, Massachusetts General Hospital, Harvard Medical School)

  • Henry M. Kronenberg

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • David Lagares

    (Center for Immunology and Inflammatory Diseases, Fibrosis Research Center, Massachusetts General Hospital, Harvard Medical School)

  • Yuhei Uda

    (Boston University)

  • Paola Divieti Pajevic

    (Boston University)

  • Mary L. Bouxsein

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School
    Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Ted S. Gross

    (University of Washington)

  • Marc N. Wein

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School
    Broad Institute of Harvard and MIT)

Abstract

Osteocytes, cells ensconced within mineralized bone matrix, are the primary skeletal mechanosensors. Osteocytes sense mechanical cues by changes in fluid flow shear stress (FFSS) across their dendritic projections. Loading-induced reductions of osteocytic Sclerostin (encoded by Sost) expression stimulates new bone formation. However, the molecular steps linking mechanotransduction and Sost suppression remain unknown. Here, we report that class IIa histone deacetylases (HDAC4 and HDAC5) are required for loading-induced Sost suppression and bone formation. FFSS signaling drives class IIa HDAC nuclear translocation through a signaling pathway involving direct HDAC5 tyrosine 642 phosphorylation by focal adhesion kinase (FAK), a HDAC5 post-translational modification that controls its subcellular localization. Osteocyte cell adhesion supports FAK tyrosine phosphorylation, and FFSS triggers FAK dephosphorylation. Pharmacologic FAK catalytic inhibition reduces Sost mRNA expression in vitro and in vivo. These studies demonstrate a role for HDAC5 as a transducer of matrix-derived cues to regulate cell type-specific gene expression.

Suggested Citation

  • Tadatoshi Sato & Shiv Verma & Christian D. Castro Andrade & Maureen Omeara & Nia Campbell & Jialiang S. Wang & Murat Cetinbas & Audrey Lang & Brandon J. Ausk & Daniel J. Brooks & Ruslan I. Sadreyev & , 2020. "A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17099-3
    DOI: 10.1038/s41467-020-17099-3
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    Cited by:

    1. Jialiang S. Wang & Tushar Kamath & Courtney M. Mazur & Fatemeh Mirzamohammadi & Daniel Rotter & Hironori Hojo & Christian D. Castro & Nicha Tokavanich & Rushi Patel & Nicolas Govea & Tetsuya Enishi & , 2021. "Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin," Nature Communications, Nature, vol. 12(1), pages 1-20, December.

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