Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis
Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis
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DOI：
10.1038/s41467-019-14076-3
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发表时间：
2020-01-23
影响因子：
16.6
通讯作者：
Wu, Zhao-Qiu
中科院分区：
文献类型：
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作者：
Fu, Rong;Lv, Wen-Cong;Wu, Zhao-Qiu
最近对骨代谢控制的兴趣集中在CD 31（hi）内粘蛋白（hi）血管的一个专门子集上，据报道，这些血管将血管生成与骨生成偶联。然而，将这些过程联系在一起的基本机制在很大程度上仍不明确。我们发现锌指转录因子ZEB 1主要表达于人和小鼠骨的CD 31（hi）内皮粘蛋白（hi）。内皮细胞特异性缺失ZEB 1可损害骨中CD 31（hi）内粘蛋白（hi）血管形成，导致骨生成减少。从机制上讲，ZEB 1缺失减少了Dll 4和Notch 1启动子上的组蛋白乙酰化，从而在表观遗传学上抑制Notch信号传导，这是控制骨血管生成和骨生成的关键途径。ZEB 1在骨质疏松小鼠和人类骨骼内皮细胞中的表达下降。在骨质疏松小鼠中施用Zeb 1包装的脂质体可恢复骨骼内皮中受损的Notch活性，从而促进血管生成依赖性骨生成并改善骨丢失。低ZEB 1/Notch信号的药理学逆转可能通过促进血管生成依赖性骨形成而在骨质疏松患者中发挥治疗益处。已经报道了表达内粘蛋白和CD 31的内皮细胞亚型将血管生成与骨生成偶联。在这里，作者表明，这些细胞中ZEB 1的缺失在表观遗传学上抑制了Notch信号传导，导致血管生成和骨生成受损，并且通过脂质体递送Zeb 1改善了骨质疏松小鼠的骨丢失
Recent interest in the control of bone metabolism has focused on a specialized subset of CD31(hi)endomucin(hi) vessels, which are reported to couple angiogenesis with osteogenesis. However, the underlying mechanisms that link these processes together remain largely undefined. Here we show that the zinc-finger transcription factor ZEB1 is predominantly expressed in CD31(hi)endomucin(hi) endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31(hi)endomucin(hi) vessel formation in the bone, resulting in reduced osteogenesis. Mechanistically, ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, thereby epigenetically suppressing Notch signaling, a critical pathway that controls bone angiogenesis and osteogenesis. ZEB1 expression in skeletal endothelium declines in osteoporotic mice and humans. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. Pharmacological reversal of the low ZEB1/Notch signaling may exert therapeutic benefit in osteoporotic patients by promoting angiogenesis-dependent bone formation. An endothelial cell subtype, expressing endomucin and CD31, has been reported to couple angiogenesis with osteogenesis. Here, the authors show that loss of ZEB1 in these cells epigenetically suppresses Notch signaling, leading to impaired angiogenesis and osteogenesis, and that Zeb1 delivery via liposomes ameliorates bone loss in osteoporotic mice