Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice.

Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associated Shank3 knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specific Shank3 conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)- mediated in vivo gene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediated Shank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion of Shank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.

Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

Transgenerational inheritance of wing development defects in Drosophila melanogaster induced by cadmium.

The transgenerational inheritance of phenotype induced by environmental factors is a new focus in epigenetic research. In this study, Drosophila melanogaster (F0) was cultured in the medium containing cadmium (Cd, 4.5 mg/kg) from eggs to adults, and offspring (F1-F4) were continuously kept in standard medium (without cadmium). The phenotype analysis showed that cadmium induced developmental defects on wings and apoptosis in the wing disc cells of Drosophila (F0). The wing defects were transmitted for at least four generations even without Cd afterwards. And the effect on the mRNA expression of wing development related genes (shg, omb, F-actin, Mekk1) can be maintained for at least two or three generations. More importantly, under cadmium stress, the post-translational modification (PTM) on the histones H3K4me3 in the third instar larvae and ovaries or testes of adult flies increased significantly, while the levels of H3K9me3 and H3K27me3 decreased significantly. The expression of histone methylation related genes (dSet-1, ash1, Lsd1) increased significantly and these changes can be transmitted to offspring from one or two generations in ovaries or testes. These results suggest that the phenotypic defects of wings caused by cadmium can be inherited to the offspring, and this transgenerational inheritance effect may be related to the epigenetic regulation of histone methylation. Therefore, the adaptability of offspring should be considered when evaluating the toxicity and environmental risk of cadmium.

Identification of novel factors that affect the onset of idiopathic chronic pancreatitis: The role for microRNA-323b-5p.

BACKGROUND: The c.194+2 T>C variant of serine protease inhibitor Kazal type 1 (SPINK1) is a known genetic risk factor found in Chinese patients with idiopathic chronic pancreatitis (ICP), but the early-onset mechanisms of ICP are still unclear. METHODS: Complementary experimental approaches were used to pursue other potential pathologies in the present study. The serum level of SPINK1 of ICP patients in the Han population in China was detected and verified by an enzyme-linked immunosorbent assay. Next, differentially expressed proteins and microRNAs from plasma samples of early-onset and late-onset ICP patients were screened by proteomic analysis and microarray, respectively. RESULTS: Combined with these advanced methods, the data strongly suggest that the regulatory effects of microRNAs were involved in the early-onset mechanism of the ICP by in vitro experiments. There was no significant difference in the plasma SPINK1 expression between the early-onset ICP and the late-onset patients. However, the expression of plasma glutathione peroxidase (GPx3) in early-onset ICP patients was markedly lower than that in late-onset ICP patients, although the level of hsa-miR-323b-5p was lower in late-onset patients compared to the early-onset ICP group. In vitro experiments confirmed that hsa-miR-323b-5p could increase apoptosis in caerulein-treated pancreatic acinar cells and inhibit the expression of GPx3. CONCLUSIONS: The up-regulated hsa-miR-323b-5p might play a crucial role in the early-onset mechanisms of ICP by diminishing the antioxidant activity through the down-regulation of GPx3.

NF1 Gene Novel Splicing Mutations in a Chinese Family with Neurofibromatosis Type 1: Case Series.

Background: Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder. NF1 is a multisystemic disease and its pathogenesis involves mutations in the NF1 gene on chromosome 17q11.2 causing RAS overactivation to stimulate abnormal cell proliferation. Purpose: To identify pathogenic mutation of the NF1 gene in a pedigree of NF1. Patients and Methods: Collection of clinical data from one NF1 family. Peripheral blood samples were collected from the affected persons and their family members. Potential mutations of NF1 gene were screened by exome and cDNA sequencing. Results: A splice mutation (c.4836-10T>G) was found in exon 37 of the NF1 gene in this NFI family, and no corresponding mutation was found in healthy members of this pedigree or in the human reference genome (GRCh37/hg19). Conclusion: Mutations of NF1 gene is a major cause of NF1. The novel splice mutation in exon 37 of NF1 gene is the underlying cause of the familial c.4836-10T>G.

SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/ß-catenin signaling.

Breast cancer stem cells (BCSCs) are the main drivers of recurrence and metastasis. However, commonly used drugs rarely target BCSCs. Via screenings, we found that Salt-inducible kinase 2 (SIK2) participated in breast cancer (BC) stemness maintenance and zebrafish embryos development. SIK2 was upregulated in recurrence samples. Knockdown of SIK2 expression reduced the proportion of BCSCs and the tumor initiation of BC cells. Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/ß-catenin signaling pathway activation. ARN-3236 and HG-9-91-01, inhibitors of SIK2, inhibited LRP6 phosphorylation and ß-catenin accumulation and disturbed stemness maintenance. In addition, the SIK2-activated Wnt/ß-catenin signaling led to induction of IDH1 expression, causing metabolic reprogramming in BC cells. These findings demonstrate a novel mechanism whereby Wnt/ß-catenin signaling pathway is regulated by different kinases in response to metabolic requirement of CSCs, and suggest that SIK2 inhibition may potentially be a strategy for eliminating BCSCs.

Proteome-centric cross-omics characterization and integrated network analyses of triple-negative breast cancer.

We report a comprehensive proteomic study of a 90-case cohort of paired samples of triple-negative breast cancer (TNBC) in quantification, phosphorylation, and DNA-binding capacity. Four integrative subtypes (iP-1-4) are stratified on the basis of global proteome and phosphoproteome, each of which exhibits distinct molecular and pathway features. Scaffold and co-expression network analyses of three proteomic datasets, integrated with those from genome and transcriptome of the same cohort, reveal key pathways and master regulators that, characteristic of TNBC subtypes, play important regulatory roles within and between scaffold sub-structures and co-expression communities. We find that NAE1 is a potential drug target for subtype iP-1, and a series of key molecules in fatty acid metabolism, such as AKT1/FASN, are plausible targets for subtype iP-2. Libraries of proteins, pathways and networks of TNBC provide a valuable molecular infrastructure for further clinical exploration and in-depth studies of the molecular mechanisms of the disease.

Pantothenate Kinase 1 Inhibits the Progression of Hepatocellular Carcinoma by Negatively Regulating Wnt/ß-catenin Signaling.

Hyperactivation of Wnt/ß-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms underlying the hyperactivation of Wnt/ß-catenin signaling are incompletely understood. In this study, Pantothenate kinase 1 (PANK1) is shown to be a negative regulator of Wnt/ß-catenin signaling. Downregulation of PANK1 in HCC correlates with clinical features. Knockdown of PANK1 promotes the proliferation, growth and invasion of HCC cells, while overexpression of PANK1 inhibits the proliferation, growth, invasion and tumorigenicity of HCC cells. Mechanistically, PANK1 binds to CK1α, exerts protein kinase activity and cooperates with CK1α to phosphorylate N-terminal serine and threonine residues in ß-catenin both in vitro and in vivo. Additionally, the expression levels of PANK1 and ß-catenin can be used to predict the prognosis of HCC. Collectively, the results of this study highlight the crucial roles of PANK1 protein kinase activity in inhibiting Wnt/ß-catenin signaling, suggesting that PANK1 is a potential therapeutic target for HCC.

The Protein Kinase Activity of NME7 Activates Wnt/ß-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma.

Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/ß-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/ß-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/ß-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, whereas overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and to promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3ß to promote ß-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of ß-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. In addition, expression levels of NME7, ß-catenin, and MTHFD2 correlated with each other and with poor prognosis in patients with HCC. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/ß-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC. SIGNIFICANCE: The identification of NME7 as an activator of Wnt/ß-catenin signaling and MTHFD2 expression in HCC reveals a mechanism regulating one-carbon metabolism and potential therapeutic strategies for treating this disease.

Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors.

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.

The effects of cadmium on the development of Drosophila and its transgenerational inheritance effects.

A new focus in toxicology research is the impact of parental exposure to environmental toxic substances on the characteristics of offspring. In the present study, newly produced eggs of Drosophila melanogaster were treated with different concentrations of cadmium (0, 1, 2, 4, 8 mg/kg) to study the effects of development. The results showed that cadmium changed the larval body length and weight, prolonged the pupation and eclosion time, and changed the relative expression levels of development-related genes (baz, ß-Tub60D, tj). Furthermore, the parental Drosophila (F0) were treated with cadmium (4.5 mg/kg) from egg stage, and when grows to adults, they mated in standard medium to produce the de-stressed offspring (F1-F4) to assess the transgenerational effects of developmental delay. The results showed that the delayed effects of the pupation and eclosion time could be maintained for two generations, and the inhibiting effects of juvenile hormone (JH) and ecdysone (20-hydroxyecdysone, 20E) could be maintained for two or three generations. More importantly, cadmium increased the expression of DNA methylation-related genes (dDnmt2, dMBD2/3) in the ovaries (F0-F2) and testicles (F0 and F1). In addition, cadmium accumulated in parental Drosophila (F0) was not transmitted to offspring through reproductive pathway. These results demonstrate that the developmental toxicity caused by cadmium could be transmitted to the de-stressed offspring, and the observed transgenerational inheritance effects may be associated with epigenetic regulation, underscoring the need to consider fitness of future generations in evaluating the toxicity and environmental risks of cadmium.

Laryngeal Helicobacter pylori Infection and Laryngeal Cancer-Case Series and a Systematic Review.

Helicobacter pylori (H. pylori) infection involves the development of gastric cancer and may be associated with laryngeal cancer. However, laryngeal H. pylori infection in Taiwanese patients with newly diagnosed laryngeal cancer has not been reported. This study was aimed to investigate the possible association between laryngeal H. pylori infection and laryngeal cancer in Taiwan and perform a systematic review of previous reports in other countries. An analysis of 105 patients with laryngeal lesions found the positive rates of H. pylori DNA (determined by polymerase chain reaction) and antigen (determined by immunohistochemistry) of the laryngeal lesions were relatively low (vocal polyps: 3% and 3%; vocal fold leukoplakia: 0% and 0%; laryngeal cancers: 0% and 2%). Furthermore, H. pylori-associated laryngopharyngeal reflux and the expression of E-cadherin and CD1d (determined by immunohistochemistry) were comparable among the three subgroups. Fifteen studies were involved in the systematic review of the digital literature database, distributed to February 2021. The data of patients with laryngeal cancer and controls showed that the laryngeal H. pylori infection rates were 29.4% and 16.7%, respectively. Although current evidence supported that laryngeal H. pylori infection was associated with laryngeal cancer globally, it might not play a role in the development of laryngeal cancer in Taiwan.

Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology.

LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.

Human growth hormone proteoform pattern changes in pituitary adenomas: Potential biomarkers for 3P medical approaches.

RELEVANCE: Human growth hormone (hGH) is synthesized, stored, and secreted by somatotroph cells in the pituitary gland, and promotes human growth and metabolism. Compared to a normal pituitary, a GH-secreting pituitary adenoma can secrete excessive GH to cause pathological changes in body tissues. GH proteoform changes would be associated with GH-related disease pathogenesis. PURPOSE: This study aimed to elucidate changes in GH proteoforms between GH-secreting pituitary adenomas and control pituitaries for the predictive diagnostics, targeted prevention, and personalization of medical services. METHODS: The isoelectric point (pI) and relative molecular mass (Mr) are two basic features of a proteoform that can be used to effectively array and detect proteoforms with two-dimensional gel electrophoresis (2DGE) and 2DGE-based western blot. GH proteoforms were characterized with liquid chromatography (LC) and mass spectrometry (MS). Phosphoproteomics, ubiquitinomics, acetylomics, and bioinformatics were used to analyze post-translational modifications (PTMs) of GH proteoforms in GH-secreting pituitary adenoma tissues and control pituitaries. RESULTS: Sixty-six 2D gel spots were found to contain hGH, including 46 spots (46 GH proteoforms) in GH-secreting pituitary adenomas and 35 spots (35 GH proteoforms) in control pituitaries. Further, 35 GH proteoforms in control pituitary tissues were matched with 35 of 46 GH proteoforms in GH-secreting pituitary adenoma tissues; and 11 GH proteoforms were presented in only GH-secreting pituitary adenoma tissues but not in control pituitary tissues. The matched 35 GH proteoforms showed quantitative changes in GH-secreting pituitary adenomas compared to the controls. The quantitative levels of those 46 GH proteoforms in GH-secreting pituitary adenomas were significantly different from those 35 GH proteoforms in control pituitaries. Meanwhile, different types of PTMs were identified among those GH proteoforms. Phosphoproteomics identified phosphorylation at residues Ser77, Ser132, Ser134, Thr174, and Ser176 in hGH. Ubiquitinomics identified ubiquitination at residue Lys96 in hGH. Acetylomics identified acetylation at reside Lys171 in hGH. Deamination was identified at residue Asn178 in hGH. CONCLUSION: These findings provide the first hGH proteoform pattern changes in GH-secreting pituitary adenoma tissues compared to control pituitary tissues, and the status of partial PTMs in hGH proteoforms. Those data provide in-depth insights into biological roles of hGH in GH-related diseases, and identify hGH proteoform pattern biomarkers for treatment of a GH-secreting pituitary adenoma in the context of 3P medicine -predictive diagnostics, targeted prevention, and personalization of medical services. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00232-7.

Endoscopic submucosal dissection versus esophagectomy for early esophageal squamous cell carcinoma with tumor invasion to different depths.

Endoscopic submucosal dissection (ESD) is a minimally invasive alternative to esophagectomy for early esophageal squamous cell carcinoma (EESCC). The aim of this study was to compare the efficacy and safety of ESD and esophagectomy in EESCC with different depth of invasion. The data of EESCC patients who received ESD or esophagectomy between Jan 2011 to Dec 2018 at our center were retrospectively analyzed. Overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), and procedure-related variables were compared between ESD and esophagectomy patients. 222 EESCC patients underwent ESD, while 184 underwent esophagectomy. No significant differences were found between the two groups in OS (P=0.417), DSS (P=0.423), and RFS (P=0.726). Procedure duration, post-procedure hospital stay, and hospitalization cost were all lower in ESD patients. Oncologic outcomes were similar between the two groups in propensity score-matched analysis. The R0 resection rate was comparable between ESD and esophagectomy groups in the T1a-M1/M2 and M3/SM1 EESCC subgroups; no significant differences were found in OS, DSS and RFS. In the SM2/SM3 EESCC subgroup, although the prognosis of the two treatment groups was similar, the R0 resection rate was significantly lower in ESD patients than in esophagectomy patients. Thus, we concluded ESD could be a first-line treatment for T1a-M1/M2 and M3/SM1 EESCC as oncologic outcome is comparable to that achieved with esophagectomy with minimal invasion, lower cost and lower incidence of serious adverse events. However, in SM2/SM3 EESCC patients, esophagectomy may be preferable.

m6A Reader YTHDC2 Promotes Radiotherapy Resistance of Nasopharyngeal Carcinoma via Activating IGF1R/AKT/S6 Signaling Axis.

N6-methyladenosine (m6A) modification has been reported as a critical regulator of gene transcript expression. Although m6A modification plays important roles in tumor development, its role in therapeutic resistance remains unknown. In this study, we aimed to examine the expression level of m6A-modification related proteins and elucidate the effect of m6A-related proteins on radiation response in nasopharyngeal carcinoma (NPC). Among the genes that participated in m6A modification, YTHDC2, a m6A reader, was found to be consistently highly expressed in radioresistant NPC cells. Knocking down of YTHDC2 expression in radioresistant NPC cells improved the therapeutic effect of radiotherapy in vitro and in vivo, whereas overexpression of YTHDC2 in radiosensitive NPC cells exerted an opposite effect. Bioinformatics and mechanistic studies revealed that YTHDC2 could physically bound to insulin-like growth factor 1 receptor (IGF1R) messenger RNA and promoted translation initiation of IGF1R mRNA, which in turn activated the IGF1R-AKT/S6 signaling pathway. Thus, the present study suggests that YTHDC2 promotes radiotherapy resistance of NPC cells by activating the IGF1R/ATK/S6 signaling axis and may serve as a potential therapeutic target in radiosensitization of NPC cells.

Acute liver abscess after non-operative management of blunt liver injury: A rare case managed with laparoscopic drainage.

INTRODUCTION: Liver abscess may develop as a rare complication of the non-operative management (NOM) of blunt liver injury. PRESENTATION: A 36-year-old male was injured in a motorcycle accident on November 28, 2017. First aid was performed at the local hospital, then he was transferred to our trauma center for further management. The abdominal computed tomography (CT) revealed a segment 7/8 liver laceration, and the liver injury was of grade III according to the American Association for the Surgery of Trauma-Organ Injury Scale for liver injury. Intermittent high fever was observed for the first 3 days after NOM, and repeat abdominal CT showed an abscess with rupture at the previously injured liver parenchyma. He underwent laparoscopic drainage of the liver abscess, and culture revealed the presence of Salmonella enterica, serogroup D. After laparoscopic drainage, the patient recovered well, with a 21-day hospital stay. DISCUSSION: Liver abscess as a complication after NOM of blunt liver injury is a rare entity, with an incidence rate of 1.5%. It is usually seen in major liver injuries (grade III and above) and the abscesses take a median of 6 days (range, 1-12 days) to form and be diagnosed. The management of liver abscess may be by surgical drainage (laparotomy or laparoscopy) or percutaneous drainage. CONCLUSION: This report reminds us the liver abscess complication after NOM of blunt liver injury, although it is a rare entity. Results of this patient support drainage of the liver abscess can be safely and effectively performed by laparoscopy.

Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma.

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.

Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis.

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.