A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction

Nat Commun. 2020 Jul 1;11(1):3282. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Focal Adhesion Protein-Tyrosine Kinases / genetics*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Gene Expression Profiling / methods
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Humans
  • Mechanotransduction, Cellular / genetics*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteocytes / metabolism*
  • Osteogenesis / genetics
  • Phosphorylation
  • Signal Transduction / genetics*


  • Focal Adhesion Protein-Tyrosine Kinases
  • Hdac5 protein, mouse
  • Histone Deacetylases