Lysine-specific demethylase 1 inhibitor rescues the osteogenic ability of mesenchymal stem cells under osteoporotic conditions by modulating H3K4 methylation.
Lysine-specific demethylase 1 inhibitor rescues the osteogenic ability of mesenchymal stem cells under osteoporotic conditions by modulating H3K4 methylation.
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DOI：
10.1038/boneres.2016.37
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发表时间：
2016
期刊：
影响因子：
12.7
通讯作者：
Zhou, Yongsheng
中科院分区：
文献类型：
--
作者：
Lv, Longwei;Ge, Wenshu;Liu, Yunsong;Lai, Guanyou;Liu, Hao;Li, Wenyue;Zhou, Yongsheng
骨组织工程可能受到潜在骨质疏松症的阻碍，因为这些患者的自体种子细胞成骨能力下降和不利的微环境改变。表观遗传调控在骨质疏松的发育起源中起重要作用；然而，很少有研究调查表观遗传疗法在骨质疏松症条件下改善或恢复骨髓间充质干细胞（BMMSCs）成骨能力的潜力。在这里，我们研究了pargyline，一种赖氨酸特异性去甲基酶1 （LSD1）的抑制剂，它主要催化H3K4二甲基化和单甲基化的去甲基化。我们证明1.5 mmol·L−1 pargyline是人骨髓间充质干细胞成骨分化的最佳浓度。Pargyline通过提高成骨相关基因启动子区域H3K4的二甲基化水平，挽救了骨质疏松条件下小鼠BMMSCs的成骨分化能力。此外，pargyline在老年或去卵巢小鼠模型中分别部分挽救或预防骨质疏松。通过将表观遗传治疗的概念引入骨质疏松症领域，本研究证明LSD1抑制剂可以改善基于msc的骨组织工程的临床实践，并提出其治疗骨质疏松症的新用途。
Bone tissue engineering may be hindered by underlying osteoporosis because of a decreased osteogenic ability of autologous seed cells and an unfavorably changed microenvironment in these patients. Epigenetic regulation plays an important role in the developmental origins of osteoporosis; however, few studies have investigated the potential of epigenetic therapy to improve or rescue the osteogenic ability of bone marrow mesenchymal stem cells (BMMSCs) under osteoporotic conditions. Here, we investigated pargyline, an inhibitor of lysine-specific demethylase 1 (LSD1), which mainly catalyzes the demethylation of the di- and mono-methylation of H3K4. We demonstrated that 1.5 mmol·L−1 pargyline was the optimal concentration for the osteogenic differentiation of human BMMSCs. Pargyline rescued the osteogenic differentiation ability of mouse BMMSCs under osteoporotic conditions by enhancing the dimethylation level of H3K4 at the promoter regions of osteogenesis-related genes. Moreover, pargyline partially rescued or prevented the osteoporotic conditions in aged or ovariectomized mouse models, respectively. By introducing the concept of epigenetic therapy into the field of osteoporosis, this study demonstrated that LSD1 inhibitors could improve the clinical practice of MSC-based bone tissue engineering and proposes their novel use to treat osteoporosis.
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影响因子：
12.3
作者：
Peng B
通讯作者：
Peng B
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影响因子：
--
作者：
Liu Y;Tian M;Zhang H
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影响因子：
12.7
作者：
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通讯作者：
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影响因子：
64.5
作者：
Ducy, P;Amling, M;Karsenty, G
通讯作者：
Karsenty, G