Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo.

Abstract

AIM:

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.

CONCLUSION:

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: Song Xu, Kim De Veirman, Holly Evans, Gaia Cecilia Santini, Isabelle Vande Broek, Xavier Leleu, Ann De Becker, Ben Van Camp, Peter Croucher, Karin Vanderkerken, Ivan Van Riet
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 34 Issue 5 Pg. 699-709 (May 2013) ISSN: 1745-7254 [Electronic] United States
• PMID: 23564084 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Vorinostat

Topics

• Animals
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cells, Cultured
• Histone Deacetylase Inhibitors (adverse effects, pharmacology)
• Humans
• Hydroxamic Acids (adverse effects, pharmacology)
• Mesenchymal Stem Cells (cytology, drug effects)
• Mice
• Mice, Inbred C57BL
• Multiple Myeloma (drug therapy)
• Osteogenesis (drug effects)
• Vorinostat