The anti-Myeloma drug Vorinostat promotes osteogenic differentiation of mesenchymal stem cells (MSCS)

We have recently shown that bone marrow-derived MSCs from MM patients exhibited much lower osteogenic differentiation ability compared to normal MSCs. Recent studies indicated that novel anti-MM agents not only target the MM cell directly but also affect the BM microenvironment. Vorinostat is the only HDAC inhibitor drug currently used in clinical phase I/II trials for MM patients. In the present study, we found that Vorinostat increased in bone marrow MSCs from both MM patients and normal donors, in a concentration dependent manner (0-1µM), the activity of alkaline phosphatase (ALP), which is an early marker of osteoblast differentiation. This osteogenesis-promoting effect was also confirmed by PCR analysis for osteogenic markers (OPN, ALP, BSP, BMP2 and OTX) and matrix mineralization. Importantly, we found that Vorinostat upregulates Runx2 expression of MSCs which is a key transcription factor for osteoblastogenesis. Vorinostat increased, even without exogeneous osteogenic stimuli, ac-H3 and p21 expression of MSCs, but suppressed HDAC1 and HDAC4 activity, mimicking natural epigenetic alteration duringMSCs osteogenic differentation. We observed that Vorinostat affected in vitro MSCs viability with an IC50 of 15.57µM, while the observed IC50 for myeloma cells RPMI8226, Karpas and U266 was 0.71µM, 0.24µM and 1.29µM, respectively, indicating that MSCs are much more resistant to the action of this drug. The effect of vorinostat on MSCs osteogenesis in vivo is currently under investigation.