Induction of osteogenic differentiation of human mesenchymal stem cells by histone deacetylase inhibitors
Induction of osteogenic differentiation of human mesenchymal stem cells by histone deacetylase inhibitors
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DOI：
10.1002/jcb.20544
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发表时间：
2005-10-15
影响因子：
4
通讯作者：
Jung, JS
中科院分区：
文献类型：
--
作者：
Cho, HH;Park, HT;Jung, JS
丙戊酸(VPA)几十年来一直被用作治疗癫痫的抗惊厥药物，以及治疗双相情感障碍的情绪稳定剂。这些效应的作用机制仍有待阐明，很可能是多因素作用的。近年来，VPA被报道抑制组蛋白脱乙酰酶(HDAC)，并且HDAC被报道在哺乳动物细胞分化中发挥作用。本研究检测了HDAC抑制剂对人脂肪组织来源的基质细胞(HADSC)和骨髓基质细胞(HBMSC)分化和增殖的影响。VPA以剂量依赖的方式促进成骨分化。VPA诱导分化前的预处理对hMSC的成骨分化也有促进作用。另一种HDAC抑制剂曲古抑菌素A(TSA)也能促进hADSC的成骨分化，而结构类似于VPA但不具有HDAC抑制作用的丙普罗胺(VPM)对hADSC的成骨分化没有任何影响。RT-PCR和Real-time PCR分析显示，VPA处理后骨桥蛋白、BMP-2、Osterix和Runx2的表达增加。加入noggin可抑制VPA诱导的成骨分化作用。VPA可抑制hADSC和hBMSC的增殖。我们的结果表明，VPA促进成骨分化，可能是由于抑制了HDAC，并可能用于体内hMSC的骨工程。
Valproic acid (VPA) has been used as an anticonvulsant agent for the treatment of epilepsy, as well as a mood stabilizer for the treatment of bipolar disorder, for several decades. The mechanism of action for these effects remains to be elucidated and is most likely multifactorial. Recently, VPA has been reported to inhibit histone deacetylase (HDAC) and HDAC has been reported to play roles in differentiation of mammalian cells. In this study, the effects of HDAC inhibitors on differentiation and proliferation of human adipose tissue-derived stromal cells (hADSC) and bone marrow stromal cells (hBMSC) were determined. VPA increased osteogenic differentiation in a dose dependent manner. The pretreatment of VPA before induction of differentiation also showed stimulatory effects on osteogenic differentiation of hMSC. Trichostatin A (TSA), another HDAC inhibitor, also increased osteogenic differentiation, whereas valpromide (VPM), a structural analog of VPA which does not possess HDAC inhibitory effects, did not show any effect on osteogenic differentiation on hADSC. RT-PCR and Real-time PCR analysis revealed that VPA treatment increased osterix, osteopontin, BMP-2, and Runx2 expression. The addition of noggin inhibited VPA-induced potentiation of osteogenic differentiation. VPA inhibited proliferation of hADSC and hBMSC. Our results suggest that VPA enhance osteogenic differentiation, probably due to inhibition of HDAC, and could be useful for in vivo bone engineering using hMSC.