title: A Novel Osteogenic Activity of Suberoylanilide Hydroxamic Acid is Synergized by BMP-2.
abstract: BACKGROUND
  Many histone deacetylase (HDAC) inhibitors are well recognized as potential anti-cancer drugs. Inhibition of HDACs induces temporal transcription or epigenetic control, thus regulating many different biological responses. Here, we investigated the osteogenic effect of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat).
  
  
  METHODS
  The effects of SAHA on osteoblast differentiation were examined in the 6XOSE-Luc reporter assay for determination of runt-related transcription factor 2 (Runx2) activity and alkaline phosphatase (ALP) activity and in an immunoprecipitation assay to determine the Runx2 acetylation state. The osteogenic activity of SAHA in vivo was studied in and receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoporotic mouse model.
  
  
  RESULTS
  SAHA increased the transcriptional activity of Runx2 in a dose-dependent manner in the 6XOSE-Luc reporter assay. SAHA by itself was unable to induce ALP activity; however, SAHA enhanced ALP activity induced by bone morphogenetic protein-2 (BMP-2). The degree of acetylation of Runx2 was increased with SAHA treatment, which suggests that the increase in Runx2 transcriptional activity might be dependent on stabilization by acetylation. Also, SAHA successfully reversed soluble RANKL-induced osteoporotic bone loss.
  
  
  CONCLUSIONS
  Our study shows an intriguing osteogenic potential of SAHA in a BMP-2-dependent manner and suggests that SAHA could be used at lower doses along with BMP-2 to treat osteoporosis.
authors.affiliation: Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.affiliation: Bone Research Institute, BioRunx Co. Ltd., Seoul, Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Molecular Genetics, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: Hyun Mo
authors.initials: HM
authors.lastname: Ryoo
keywords: Bone morphogenetic protein 2; Histone deacetylase inhibitors; Osteogenesis