Effects of histone deacetylase inhibitor Scriptaid and parathyroid hormone on osteocyte functions and metabolism

J Biol Chem. 2019 Jun 21;294(25):9722-9733. doi: 10.1074/jbc.RA118.007312. Epub 2019 May 8.


Bone is a highly metabolic organ that undergoes continuous remodeling to maintain its structural integrity. During development, bones, in particular osteoblasts, rely on glucose uptake. However, the role of glucose metabolism in osteocytes is unknown. Osteocytes are terminally differentiated osteoblasts orchestrating bone modeling and remodeling. In these cells, parathyroid hormone (PTH) suppresses Sost/sclerostin expression (a potent inhibitor of bone formation) by promoting nuclear translocation of class IIa histone deacetylase (HDAC) 4 and 5 and the repression of myocyte enhancer factor 2 (MEF2) type C. Recently, Scriptaid, an HDAC complex co-repressor inhibitor, has been shown to induce MEF2 activation and exercise-like adaptation in mice. In muscles, Scriptaid disrupts the HDAC4/5 co-repressor complex, increases MEF2C function, and promotes cell respiration. We hypothesized that Scriptaid, by affecting HDAC4/5 localization and MEF2C activation, might affect osteocyte functions. Treatment of the osteocytic Ocy454-12H cells with Scriptaid increased metabolic gene expression, cell respiration, and glucose uptake. Similar effects were also seen upon treatment with PTH, suggesting that both Scriptaid and PTH can promote osteocyte metabolism. Similar to PTH, Scriptaid potently suppressed Sost expression. Silencing of HDAC5 in Ocy454-12H cells abolished Sost suppression but not glucose transporter type 4 (Glut4) up-regulation induced by Scriptaid. These results demonstrate that Scriptaid increases osteocyte respiration and glucose uptake by mechanisms independent of HDAC complex inhibition. In osteocytes, Scriptaid, similar to PTH, increases binding of HDAC5 to Mef2c with suppression of Sost but only partially increases receptor activator of NF-κB ligand (Rankl) expression, suggesting a potential bone anabolic effect.

Keywords: MEF2; SOST; Scriptaid; bone; cell metabolism; glucose transporter type 4 (GLUT4); histone deacetylase (HDAC); osteocyte; parathyroid hormone.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Calcium-Regulating Hormones and Agents / pharmacology
  • Cells, Cultured
  • Female
  • Gene Expression Regulation / drug effects*
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Hydroxylamines / pharmacology*
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteocytes / cytology
  • Osteocytes / drug effects
  • Osteocytes / metabolism*
  • Parathyroid Hormone / pharmacology*
  • Quinolines / pharmacology*


  • Adaptor Proteins, Signal Transducing
  • Calcium-Regulating Hormones and Agents
  • Glucose Transporter Type 4
  • Histone Deacetylase Inhibitors
  • Hydroxylamines
  • MEF2 Transcription Factors
  • Mef2c protein, mouse
  • Parathyroid Hormone
  • Quinolines
  • Slc2a4 protein, mouse
  • Sost protein, mouse
  • scriptaid
  • Hdac5 protein, mouse
  • Histone Deacetylases