Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis

Rong Fu, Wen-Cong Lv, Ying Xu, Mu-Yun Gong, Xiao-Jie Chen, Nan Jiang, Yan Xu, Qing-Qiang Yao, Lei Di, Tao Lu, Li-Ming Wang, Ran Mo and Zhao-Qiu Wu ()
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Rong Fu: China Pharmaceutical University
Wen-Cong Lv: China Pharmaceutical University
Ying Xu: China Pharmaceutical University
Mu-Yun Gong: China Pharmaceutical University
Xiao-Jie Chen: China Pharmaceutical University
Nan Jiang: China Pharmaceutical University
Yan Xu: The Affiliated Nanjing Hospital of Nanjing Medical University
Qing-Qiang Yao: The Affiliated Nanjing Hospital of Nanjing Medical University
Lei Di: China Pharmaceutical University
Tao Lu: China Pharmaceutical University
Li-Ming Wang: The Affiliated Nanjing Hospital of Nanjing Medical University
Ran Mo: China Pharmaceutical University
Zhao-Qiu Wu: China Pharmaceutical University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Recent interest in the control of bone metabolism has focused on a specialized subset of CD31hiendomucinhi 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 CD31hiendomucinhi endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31hiendomucinhi 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.

Date: 2020
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DOI: 10.1038/s41467-019-14076-3

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