A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction

• Published in: Nature communications Vol. 11; no. 1; pp. 3282 - 18
• Main Authors: Sato, Tadatoshi, Verma, Shiv, Andrade, Christian D. Castro, Omeara, Maureen, Campbell, Nia, Wang, Jialiang S., Cetinbas, Murat, Lang, Audrey, Ausk, Brandon J., Brooks, Daniel J., Sadreyev, Ruslan I., Kronenberg, Henry M., Lagares, David, Uda, Yuhei, Pajevic, Paola Divieti, Bouxsein, Mary L., Gross, Ted S., Wein, Marc N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/91; 631/136/815; 631/80/86; 64; 64/60; 96; 96/95; Adhesion; Animals; Biomedical materials; Bone growth; Bone matrix; Cell adhesion; Cell adhesion & migration; Cell Line; Cell Line, Tumor; Dephosphorylation; Fluid dynamics; Fluid flow; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - genetics; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Gene expression; Gene Expression Profiling - methods; Histone deacetylase; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones; Humanities and Social Sciences; Humans; In vivo methods and tests; Kinases; Localization; Mechanical loading; Mechanical stimuli; Mechanotransduction; Mechanotransduction, Cellular - genetics; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Nuclear transport; Osteocytes; Osteocytes - metabolism; Osteogenesis; Osteogenesis - genetics; Phosphorylation; Post-translation; Science; Science (multidisciplinary); Shear stress; Signal transduction; Signal Transduction - genetics; Signaling; SOST protein; Translocation; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17099-3

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. Osteocytes are mechanoresponsive within skeletal tissue. Here, the authors show that class IIa histone deacetylases are phosphorylated by focal adhesion kinase, suggesting that HDAC5 may propagate mechanobiological cues to regulate cell type-specific gene expression.