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.
Highlights
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
We observed that Zinc-finger E-box-binding homeobox 1 (ZEB1) protein was predominantly expressed in metaphyseal CD31hiEMCNhi endothelium of tibia, while it was essentially undetectable in the CD31lowEMCNlow endothelium found within the bone marrow (Fig. 1c, d)
Overexpression of ZEB1 in combination with p300 or CREB-binding protein (CBP) resulted in a 6.0 (4.1)-fold or 7.0 (5.4)-fold increase in Dll[4] (Notch1) promoter activity, respectively (Fig. 5j). These findings suggest that ZEB1 interacts with CBP/p300 in bone Endothelial cell (EC) and they co-occupy the promoters of Dll[4] and Notch[1] to enhance histone acetylation on the promoters, inducing transcriptional activation of Dll[4] and Notch[1]
Summary
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. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. The evolutionarily conserved Dll4/Notch signaling in the bone endothelium has been reported to increase CD31hiEMCNhi endothelium levels and promote bone formation by upregulating secretion levels of Noggin, a Notch-controlled angiocrine factor[2] It is currently unclear how Notch activity is tightly controlled in the bone endothelium and whether declined endothelial Notch signaling is linked to osteoporosis. The primary cell lineage(s) affected in these mice and the underlying molecular mechanisms remain undefined It remains unclear whether ZEB1 is required for postnatal bone formation or whether ZEB1 loss in certain cell lineage(s) is linked to osteoporotic disease in human and mice. Our results lay the foundation for new therapeutic strategies in osteoporosis treatment by promoting angiogenesis-dependent bone formation
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