Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis

• Published in: Nature communications Vol. 11; no. 1; p. 460
• Main Authors: Fu, Rong, Lv, Wen-Cong, Xu, Ying, Gong, Mu-Yun, Chen, Xiao-Jie, Jiang, Nan, Xu, Yan, Yao, Qing-Qiang, Di, Lei, Lu, Tao, Wang, Li-Ming, Mo, Ran, Wu, Zhao-Qiu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-01-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/176; 692/163/2743/316/801; 692/698/1671/1811; Acetylation; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - pharmacology; Aged; Angiogenesis; Animals; Biomedical materials; Blood vessels; Bone growth; Bone loss; Bone turnover; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Calcium-Binding Proteins - pharmacology; Clonal deletion; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Epigenesis, Genetic; Female; Gene deletion; Humanities and Social Sciences; Humans; Liposomes; Mice, Knockout; Mice, Transgenic; Middle Aged; multidisciplinary; Neovascularization, Physiologic - genetics; Neovascularization, Physiologic - physiology; Notch1 protein; Osteogenesis; Osteogenesis - drug effects; Osteogenesis - genetics; Osteogenesis - physiology; Osteoporosis; Osteoporosis - therapy; Ovariectomy; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Science; Science (multidisciplinary); Signaling; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism; Zinc finger proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14076-3

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
Dll
4 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