title: Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo.
abstract: OBJECTIVE
  Vorinostat, a histone deacetylase (HDAC) inhibitor currently in a clinical phase III trial for multiple myeloma (MM) patients, has been reported to cause bone loss. The purpose of this study was to test whether, and to what extent, vorinostat influences the osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro and bone formation in vivo.
  
  
  METHODS
  Bone marrow-derived MSCs were prepared from both normal donors and MM patients. The MSCs were cultured in an osteogenic differentiation induction medium to induce osteogenic differentiation, which was evaluated by alkaline phosphatase (ALP) staining, Alizarin Red S staining and the mRNA expression of osteogenic markers. Naïve mice were administered vorinostat (100 mg/kg, ip) every other day for 3 weeks. After the mice were sacrificed, bone formation was assessed based on serum osteocalcin level and histomorphometric analysis.
  
  
  RESULTS
  Vorinostat inhibited the viability of hMSCs in a concentration-dependent manner (the IC50 value was 15.57 μmol/L). The low concentration of vorinostat (1 μmol/L) did not significantly increase apoptosis in hMSCs, whereas pronounced apoptosis was observed following exposure to higher concentrations of vorinostat (10 and 50 μmol/L). In bone marrow-derived hMSCs from both normal donors and MM patients, vorinostat (1 μmol/L) significantly increased ALP activity, mRNA expression of osteogenic markers, and matrix mineralization. These effects were associated with upregulation of the bone-specifying transcription factor Runx2 and with the epigenetic alterations during normal hMSCs osteogenic differentiation. Importantly, the mice treated with vorinostat did not show any bone loss in response to the optimized treatment regimen.
  
  
  CONCLUSIONS
  Vorinostat, known as a potent anti-myeloma drug, stimulates MSC osteogenesis in vitro. With the optimized treatment regimen, any decrease in bone formation was not observed in vivo.
authors.affiliation: Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Song
authors.initials: S
authors.lastname: Xu
authors.forename: Kim
authors.initials: K
authors.lastname: De Veirman
authors.forename: Holly
authors.initials: H
authors.lastname: Evans
authors.forename: Gaia Cecilia
authors.initials: GC
authors.lastname: Santini
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vande Broek
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Ann
authors.initials: A
authors.lastname: De Becker
authors.forename: Ben
authors.initials: B
authors.lastname: Van Camp
authors.forename: Peter
authors.initials: P
authors.lastname: Croucher
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.forename: Ivan
authors.initials: I
authors.lastname: Van Riet
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy; D010012:Osteogenesis / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat
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