An HDAC Inhibitor, Entinostat/MS-275, Partially Prevents Delayed Cranial Suture Closure in Heterozygous Runx2 Null Mice

J Bone Miner Res. 2017 May;32(5):951-961. doi: 10.1002/jbmr.3076. Epub 2017 Feb 28.

Abstract

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder caused by mutations in RUNX2, coding a key transcription factor of early osteogenesis. CCD patients suffer from developmental defects in cranial bones. Despite numerous investigations and clinical approaches, no therapeutic strategy has been suggested to prevent CCD. Here, we show that fetal administration of Entinostat/MS-275, a class I histone deacetylase (HDAC)-specific inhibitor, partially prevents delayed closure of cranial sutures in Runx2+/- mice strain of C57BL/6J by two mechanisms: 1) posttranslational acetylation of Runx2 protein, which stabilized the protein and activated its transcriptional activity; and 2) epigenetic regulation of Runx2 and other bone marker genes. Moreover, we show that MS-275 stimulates osteoblast proliferation effectively both in vivo and in vitro, suggesting that delayed skeletal development in CCD is closely related to the decreased number of progenitor cells as well as the delayed osteogenic differentiation. These findings provide the potential benefits of the therapeutic strategy using MS-275 to prevent CCD. © 2017 American Society for Bone and Mineral Research.

Keywords: CLEIDOCRANIAL DYSPLASIA; HDI; MS-275; RUNX2; SKELETOGENESIS.

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Benzamides / adverse effects*
  • Benzamides / pharmacology
  • Cleidocranial Dysplasia* / chemically induced
  • Cleidocranial Dysplasia* / embryology
  • Cleidocranial Dysplasia* / genetics
  • Cleidocranial Dysplasia* / metabolism
  • Core Binding Factor Alpha 1 Subunit / genetics*
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Cranial Sutures / embryology*
  • Cranial Sutures / pathology
  • Epigenesis, Genetic / drug effects*
  • Heterozygote
  • Histone Deacetylase Inhibitors / adverse effects*
  • Histone Deacetylase Inhibitors / pharmacology
  • Mice
  • Mice, Mutant Strains
  • Protein Stability / drug effects
  • Pyridines / adverse effects*
  • Pyridines / pharmacology

Substances

  • Benzamides
  • Core Binding Factor Alpha 1 Subunit
  • Histone Deacetylase Inhibitors
  • Pyridines
  • Runx2 protein, mouse
  • entinostat