A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction

Area of Science:

• Bone biology
• Skeletal mechanobiology
• Cellular signaling

Background:

• Osteocytes are key mechanosensors in bone, detecting mechanical cues via fluid flow shear stress (FFSS).
• Reduced Sclerostin (Sost) expression by osteocytes stimulates bone formation, but the underlying molecular mechanisms are unclear.
• Class IIa histone deacetylases (HDAC4, HDAC5) are implicated in cellular responses to stimuli.

Purpose of the Study:

• To elucidate the molecular pathway linking mechanical loading to Sost suppression in osteocytes.
• To identify the role of class IIa histone deacetylases in osteocyte mechanotransduction.
• To investigate the involvement of focal adhesion kinase (FAK) in regulating Sost expression.

Main Methods:

• Utilized in vitro and in vivo models to study osteocyte responses to FFSS.
• Investigated the role of HDAC4 and HDAC5 in Sost regulation.
• Examined the phosphorylation of HDAC5 at tyrosine 642 by FAK.
• Assessed the impact of FAK inhibition on Sost mRNA expression.

Main Results:

• Class IIa HDACs (HDAC4 and HDAC5) are essential for loading-induced Sost suppression and bone formation.
• FFSS signaling induces nuclear translocation of class IIa HDACs.
• FAK directly phosphorylates HDAC5 at tyrosine 642, controlling its localization.
• FFSS triggers FAK dephosphorylation, and FAK inhibition reduces Sost expression.

Conclusions:

• HDAC5 acts as a critical transducer of mechanical cues in osteocytes.
• The FAK-HDAC5 signaling pathway mediates the response of osteocytes to FFSS.
• This pathway regulates Sost expression, thereby influencing bone formation.