A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction

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, Henry M. Kronenberg, David Lagares, Yuhei Uda, Paola Divieti Pajevic, Mary L. Bouxsein, Ted S. Gross and Marc N. Wein ()
Additional contact information
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
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
Ted S. Gross: University of Washington
Marc N. Wein: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17099-3

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