Inhibition of Histone Deacetylases Potentiates BMP9-Induced Osteogenic Signaling in Mouse Mesenchymal Stem Cells
Inhibition of Histone Deacetylases Potentiates BMP9-Induced Osteogenic Signaling in Mouse Mesenchymal Stem Cells
复制标题
抑制组蛋白脱乙酰酶可增强小鼠间充质干细胞中 BMP9 诱导的成骨信号传导
DOI：
10.1159/000354453
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发表时间：
2013-01-01
影响因子：
--
通讯作者：
Huang, Wei
中科院分区：
文献类型：
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作者：
Hu, Ning;Wang, Changdong;Huang, Wei
背景/目的：我们已证实骨形态发生蛋白9(BMP9)是调节间充质干细胞(MSCs)向成骨细胞分化的最有效的BMPs之一，但BMP9诱导成骨的分子机制尚未完全阐明。众所周知，表观遗传调控在调节干细胞潜能和谱系承诺方面发挥着重要作用。在这里，我们研究组蛋白脱乙酰酶(HDACs)的抑制是否影响BMP9诱导的MSCs的成骨分化。方法：使用HDAC抑制剂曲古抑素A(TSA)，我们评估TSA促进BMP9介导的MSCs成骨标志物和基质矿化，以及小鼠胚胎肢体外植骨的骨形成。结果：我们发现在MSCs中可以很容易地检测到11种HDAC中的大多数内源性表达。研究表明，BMP9在MSCs中诱导了大多数HDAC。我们证明TSA增强了BMP9诱导的MSCs早期成骨标志物碱性磷酸酶(ALP)的活性，以及晚期成骨标志物骨桥蛋白(OPN)和骨钙素(OCN)和基质矿化。胎儿肢体外植体培养研究表明，TSA促进BMP9诱导的软骨内骨形成，可能是通过扩大生长板肥大的软骨细胞区。结论：我们的研究结果强烈表明，组蛋白脱乙酰酶可能在通过负反馈网络微调BMP9介导的成骨信号中发挥重要作用。因此，HDAC抑制剂有可能成为治疗骨折愈合的新药物。
Background/Aims: We have demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent BMPs in regulating osteoblast differentiation of mesenchymal stem cells (MSCs) although the molecular mechanism underlying BMP9-induced osteogenesis remains to be fully elucidated. It is known that epigenetic regulations play an important role in regulating the stem cell potency and lineage commitment. Here, we investigate if the inhibition of histone deacetylases (Hdacs) affects BMP9-induced osteogenic differentiation of MSCs. Methods: Using the Hdac inhibitor trichostatin A (TSA), we assess that TSA enhances BMP9-mediated osteogenic markers and matrix mineralization in MSCs, and bone formation in mouse embryonic limb explants. Results: We find that the endogenous expression of most of the 11 Hdacs is readily detectable in MSCs. BMP9 is shown to induce most Hdacs in MSCs. We demonstrate that TSA potentiates BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs, as well as late osteogenic markers osteopontin (OPN) and osteocalcin (OCN) and matrix mineralization. Fetal limb explant culture studies reveal that TSA potentiates BMP9-induced endochondral bone formation, possibly by expanding hypertrophic chondrocyte zone of growth plate. Conclusion: Our findings strongly suggest histone deacetylases may play an important role in fine-tuning BMP9-mediated osteogenic signaling through a negative feedback network in MSCs. Thus, Hdac inhibitors may be used as novel therapeutics for bone fracture healing.