Marcella La Noce
GR-HDAC2 cytoplasmic interaction regulates osteocalcin expression enhancing bone formation
Histone deacetylases (HDACs) play a role in osteoblast differentiation of Mesenchymal Stem Cells (MSCs). In this study, MSCs treated with the HDAC inhibitor Valproic Acid (VPA) produced a well organized lamellar bone tissue in vivo, although a decrease of osteocalcin (OC) expression occurred. We investigated the molecular mechanisms by which VPA inhibits osteocalcin expression. We identified the Glucocorticoid receptor (GR) as responsible for that downregulation and suggested a correlation between GR and HDAC2 inhibition after VPA treatment, as evidenced by HDAC2 knockdown. Furthermore, co-immunoprecipitation analysis showed, as a new evidence, a binding between GR and HDAC2 in the cytoplasm. Chromatin immunoprecipitation assays confirmed the role of GR in OC downregulation, showing a recruitment of GR to the nGRE element in the OC promoter.
In conclusion, the cross-talk between the GR and HDAC2 provides a mechanistic explanation of the effect of VPA on osteocalcin expression in MSCs.
These findings open new directions in targeted therapies and offer new insights into the regulation of MSCs fate determination.