A rare skeletal dysplasia in the etiology of severe scoliosis: Diaphanospondylodysostosis.

Diaphanospondylodysostosis is a rare genetic skeletal disorder caused by biallelic variants in the BMPER gene. The term, diaphanospondylodysostosis, includes ischiospinal dysotosis, which was previously known as a distinct entity with milder clinical features. The clinical phenotype of diaphanospondylodysostosis is quite variable with mortality in early postnatal life in some patients. Main clinical and radiographic features are narrow thorax, vertebral segmentation defects, rib anomalies, ossification defects of vertebrae, ischium and sacrum, and renal cysts. In this study, we report on a 14-year-old girl patient with diaphanospondylodysostosis harbouring a novel BMPER mutation. The patient presented with severe scoliosis and severely hypoplastic/aplastic distal phalanges of the fingers and toes, findings yet hitherto not described in this syndrome.

MiR-145-5p overexpression rejuvenates aged adipose stem cells and accelerates wound healing.

Adipose-derived stem cells (ADSCs) have been widely applied in translational and regenerative medicine. During aging, there is a recognized functional decline in ADSCs, which compromises their therapeutic effectiveness. Currently, the mechanisms of aging-induced stem cell dysfunction remain unclear, hence there is a need to elucidate these mechanisms and propose strategies for reversing this functional impairment. In this study, we found that ADSCs isolated from old donors (O-ADSCs) presented inferior phenotypes and decreased miR-145-5p levels compared to those from young donors (Y-ADSCs). To interrogate the role of miR-145-5p in ADSCs, gain- and loss-of-function assays were performed. The results indicated that miR-145-5p overexpression in O-ADSCs promoted cellular proliferation and migration, while reducing cell senescence. Further study demonstrated that miR-145-5p could regulate ADSCs function by targeting bone morphogenetic protein binding endothelial cell precursor-derived regulator (BMPER), which is a crucial modulator in angiogenesis. Moreover, in vivo experiments showed that miR-145-5p-overexpressing O-ADSCs accelerated wound healing by promoting wound re-epithelialization and angiogenesis. Collectively, this study indicates that miR-145-5p works as a positive regulator for optimizing O-ADSCs function, and may be a novel therapeutic target for restoring aging-associated impairments in stem cell function.

Bone Morphogenic Proteins and Their Antagonists in the Lower Airways of Stable COPD Patients.

BACKGROUND: Bone morphogenic proteins (BMPs) and their antagonists are involved in the tissue development and homeostasis of various organs. OBJECTIVE: To determine transcriptomic and protein expression of BMPs and their antagonists in stable COPD. METHODS: We measured the expression and localization of BMPs and some relevant antagonists in bronchial biopsies of stable mild/moderate COPD (MCOPD) (n = 18), severe/very severe COPD (SCOPD) (n = 16), control smokers (CS) (n = 13), and control non-smokers (CNS) (n = 11), and in lung parenchyma of MCOPD (n = 9), CS (n = 11), and CNS (n = 9) using immunohistochemistry and transcriptome analysis, in vitro after the stimulation of the 16HBE cells. RESULTS: In bronchial biopsies, BMP4 antagonists CRIM1 and chordin were increased in the bronchial epithelium and lamina propria of COPD patients. BMP4 expression was decreased in the bronchial epithelium of SCOPD and MCOPD compared to CNS. Lung transcriptomic data showed non-significant changes between groups. CRIM1 and chordin were significantly decreased in the alveolar macrophages and alveolar septa in COPD patients. External 16HBE treatment with BMP4 protein reduced the bronchial epithelial cell proliferation. CONCLUSIONS: These data show an imbalance between BMP proteins and their antagonists in the lungs of stable COPD. This imbalance may play a role in the remodeling of the airways, altering the regenerative-reparative responses of the diseased bronchioles and lung parenchyma.

BMPER Improves Vascular Remodeling and the Contractile Vascular SMC Phenotype.

Dedifferentiated vascular smooth muscle cells (vSMCs) play an essential role in neointima formation, and we now aim to investigate the role of the bone morphogenetic protein (BMP) modulator BMPER (BMP endothelial cell precursor-derived regulator) in neointima formation. To assess BMPER expression in arterial restenosis, we used a mouse carotid ligation model with perivascular cuff placement. Overall BMPER expression after vessel injury was increased; however, expression in the tunica media was decreased compared to untreated control. Consistently, BMPER expression was decreased in proliferative, dedifferentiated vSMC in vitro. C57BL/6_Bmper+/- mice displayed increased neointima formation 21 days after carotid ligation and enhanced expression of Col3A1, MMP2, and MMP9. Silencing of BMPER increased the proliferation and migration capacity of primary vSMCs, as well as reduced contractibility and expression of contractile markers, whereas stimulation with recombinant BMPER protein had the opposite effect. Mechanistically, we showed that BMPER binds insulin-like growth factor-binding protein 4 (IGFBP4), resulting in the modulation of IGF signaling. Furthermore, perivascular application of recombinant BMPER protein prevented neointima formation and ECM deposition in C57BL/6N mice after carotid ligation. Our data demonstrate that BMPER stimulation causes a contractile vSMC phenotype and suggest that BMPER has the potential for a future therapeutic agent in occlusive cardiovascular diseases.

IL-6/Stat3 suppresses osteogenic differentiation in ossification of the posterior longitudinal ligament via miR-135b-mediated BMPER reduction.

Interleukin-6 (IL-6) has been reported to induce osteogenic differentiation of mesenchymal stem cells for increasing bone regeneration, while the role of IL-6 in osteogenic differentiation during ossification of the posterior longitudinal ligament (OPLL) remains to be determined. The current study aims to explore the downstream mechanism of IL-6 in cyclic tensile strain (CTS)-stimulated OPLL, which involves bioinformatically identified microRNA-135b (miR-135b). Initially, we clinically collected posterior longitudinal ligament (PLL) and ossified PLL tissues, from which ossified PLL cells were isolated, respectively. The obtained data revealed a greater osteogenic property of ossified PLL than non-ossified PLL cells. The effect of regulatory axis comprising IL-6, Stat3, miR-135b, and BMPER on osteogenic differentiation of CTS-stimulated ossified PLL cells was examined with gain- and loss-of-function experiments. BMPER was confirmed as a target gene to miR-135b. Knockdown of BMPER or overexpression of miR-135b inhibited the osteogenic differentiation of CTS-induced ossification in PLL cells. Besides, IL-6 promoted the post-transcriptional process to mature miR-135b via Stat3 phosphorylation. In conclusion, IL-6 inhibited CTS-induced osteogenic differentiation by inducing miR-135b-mediated inhibition of BMPER through Stat3 activation.

Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis.

Craniosynostosis (CS) is a major birth defect in which one or more skull sutures fuse prematurely. We previously performed a genome-wide association study (GWAS) for sagittal non-syndromic CS (sNCS), identifying associations downstream from BMP2 on 20p12.3 and intronic to BBS9 on 7p14.3; analyses of imputed variants in DLG1 on 3q29 were also genome-wide significant. We followed this work with a GWAS for metopic non-syndromic NCS (mNCS), discovering a significant association intronic to BMP7 on 20q13.31. In the current study, we sequenced the associated regions on 3q29, 7p14.3, and 20p12.3, including two candidate genes (BMP2 and BMPER) near some of these regions in 83 sNCS child-parent trios, and sequenced regions on 7p14.3 and 20q13.2-q13.32 in 80 mNCS child-parent trios. These child-parent trios were selected from the original GWAS cohorts if the probands carried at least one copy of the top associated GWAS variant (rs1884302 C allele for sNCS; rs6127972 T allele for mNCS). Many of the variants sequenced in these targeted regions are strongly predicted to be within binding sites for transcription factors involved in craniofacial development or bone morphogenesis. Variants enriched in more than one trio and predicted to be damaging to gene function are prioritized for functional studies.

Successfully Managed Respiratory Insufficiency in a Patient with a Novel Pathogenic Variant of the BMPER Gene: A Case Report.

Bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) gene mutation presents a disease spectrum ranging from a mild type of ischiospinal dysostosis (ISD) to a more severe type of diaphanospondylodysostosis (DSD). It is known that BMPER gene mutations are very rare, and their resulting clinical manifestations, including musculoskeletal modifications, appear in a spectrum of various types and severity levels. With the development of genetic diagnosis, case reports of patients with specific mutations in the BMPER gene have been published. The most commonly known clinical features are kidney structural problems, including neuroblastoma and renal cysts. Meanwhile, respiratory failure is a common and fatal symptom for patients with BMPER gene mutation, but it does not appear to have been well evaluated or managed so far. We report a case of a confirmed novel mutation of c.1750delT (p.Cys584fs) in the BMPER gene in a female adolescent patient and highlight the importance of the regular assessment of respiratory failure for successful management of this condition.

Diaphanospondylodysostosis: Full Case Report with Novel Pathogenic BMPER Mutation.

Diaphanospondylodysostosis is an extremely rare, recessively inherited, perinatal lethal skeletal disorder associated with BMPER gene mutations. Clinically it is characterized by defects in costovertebral ossification, absent ribs, hypertelorism, short nose with depressed nasal bridge, low-set ears, and short neck. At the extraosseous level, the most frequent pathologic finding is nephroblastomatosis with multicystic kidneys. We present the case of a child of non-consanguineous parents who died at 2 months of age in our center. Autopsy showed a marked costovertebral ossification defect, perilobar nephrogenic rests and loss of white matter with periventricular leukomalacia. After genetic study, the diagnosis of diaphanospondylodysostosis was confirmed. A previously undescribed germinal mutation in the BMPER gene (c.576 + 2dupT) was found.

BMPER alleviates ischemic brain injury by protecting neurons and inhibiting neuroinflammation via Smad3-Akt-Nrf2 pathway.

AIMS: Bone morphogenetic proteins (BMPs) are a group of proteins related to bone morphogenesis. BMP-binding endothelial regulator (BMPER), a secreted protein that interacts with BMPs, is known to be involved in ischemic injuries. Here, we explored the effects of BMPER on cerebral ischemia and its mechanism of action. METHODS: A mouse model of brain ischemia was induced by middle cerebral artery occlusion (MCAO). An in vitro ischemic model was established by subjecting primary cultured neurons to oxygen-glucose deprivation/reperfusion (OGD/R). Serum levels of BMPs/BMPER were measured in MCAO mice and in patients with acute ischemic stroke (AIS). Brain damages were compared between BMPER- and vehicle-treated mice. Quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence staining were performed to examine neuroinflammation and cell death. BMPER-related pathways were assessed by Western blotting. RESULTS: BMPER level was elevated in MCAO mice and AIS patients. BMPER administration reduced mortality, infarct size, brain edema, and neurological deficit after MCAO. Neuroinflammation and cell death after ischemia were alleviated by BMPER both in vivo and in vitro. BMPER activated the Smad3/Akt/Nrf2 pathway in OGD/R-challenged neurons. CONCLUSION: BMPER is a neuroprotective hormone that alleviates ischemic brain injury via activating the Smad3/Akt/Nrf2 pathway. These findings may provide potential therapeutic strategies for stroke.

BMP antagonists in tissue development and disease.

Bone morphogenic proteins (BMPs) are important growth regulators in embryogenesis and postnatal homeostasis. Their tight regulation is crucial for successful embryonic development as well as tissue homeostasis in the adult organism. BMP inhibition by natural extracellular biologic antagonists represents the most intensively studied mechanistic concept of BMP growth factor regulation. It was shown to be critical for numerous developmental programs, including germ layer specification and spatiotemporal gradients required for the establishment of the dorsal-ventral axis and organ formation. The importance of BMP antagonists for extracellular matrix homeostasis is illustrated by the numerous human connective tissue disorders caused by their mutational inactivation. Here, we will focus on the known functional interactions targeting BMP antagonists to the ECM and discuss how these interactions influence BMP antagonist activity. Moreover, we will provide an overview about the current concepts and investigated molecular mechanisms modulating BMP inhibitor function in the context of development and disease.

Expansion of the mutational spectrum of BMPER leading to diaphanospondylodysostosis and description of the associated disease process.

BACKGROUND: Diaphanospondylodysostosis (DSD) is a rare congenital, lethal skeletal disorder caused by recessively inherited mutations in the BMPER gene, which encodes the bone morphogenetic protein-binding endothelial cell precursor-derived regulator. The most prominent features of DSD are missing ossification of the axial skeleton, rib abnormalities and thoracic hypoplasia/insufficiency, as well as intralobar nephrogenic rests within the kidneys. METHODS: We report on the case of a 22-month-old patient with DSD where trio-exome sequencing was performed. RESULTS: Genetic testing revealed a homozygous nonsense variant c.1577G>A (p.Trp526*) in the BMPER gene, leading to a premature stop in protein translation. Both parents are asymptomatic carriers for the BMPER variant, which has not been described in the literature before. CONCLUSIONS: Our findings expand the genotypic and phenotypic spectrum of BMPER variants leading to DSD.

Identification of bone morphogenetic protein 4 in the saliva after the placement of fixed orthodontic appliance.

BACKGROUND: This study was conducted in order to explore the effects of orthodontic tooth movement (OTM) on the changes of salivary proteome. This prospective observational pilot study recruited 12 healthy teenage boys with malocclusion treated with a fixed orthodontic appliance and 6 appropriate control participants. Saliva samples were collected a day before and at 0, 2, 7, and 30 days after initialization of treatment, corresponding to the initial, lag, and post-lag phases of OTM. Pooled samples were analyzed by liquid chromatography-mass spectrometry, ELISA, and Western blotting. To date, there is no published data on the presence of BMP molecules or their antagonists in the saliva or in the gingival cervical fluid related to orthodontic conditions. RESULTS: A total of 198 identified saliva proteins were classified based on their functional characteristics. Proteins involved in bone remodeling were observed exclusively 30 days post appliance placement, including bone morphogenetic protein 4 (BMP4), a BMP antagonist BMP-binding endothelial regulator, insulin-like growth factor-binding protein 3, cytoskeleton-associated protein 4, and fibroblast growth factor 5. Based on the analysis of protein interactions, BMP4 was found to have a central position in this OTM-related protein network. CONCLUSIONS: The placement of a fixed orthodontic appliance induced occurrence of proteins involved in bone remodeling in the saliva at a time corresponding to the post-lag period of OTM. Limitations of this study include a relatively small sample size, limited time of monitoring patients, and the lack of interindividual variability assessment.

BMPER Ameliorates Renal Fibrosis by Inhibiting Tubular Dedifferentiation and Fibroblast Activation.

Tubulointerstitial fibrosis is both a pathological manifestation of chronic kidney disease and a driving force for the progression of kidney disease. A previous study has shown that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) is involved in lung fibrogenesis. However, the role of BMPER in renal fibrosis remains unknown. In the present study, the expression of BMPER was examined by real-time PCR, Western blot and immunohistochemical staining. The in vitro effects of BMPER on tubular dedifferentiation and fibroblast activation were analyzed in cultured HK-2 and NRK-49F cells. The in vivo effects of BMPER were dissected in unilateral ureteral obstruction (UUO) mice by delivery of BMPER gene via systemic administration of plasmid vector. We reported that the expression of BMPER decreased in the kidneys of UUO mice and HK-2 cells. TGF-ß1 increased inhibitor of differentiation-1 (Id-1) and induced epithelial mesenchymal transition in HK-2 cells, and knockdown of BMPER aggravated Id-1 up-regulation, E-cadherin loss, and tubular dedifferentiation. On the contrary, exogenous BMPER inhibited Id-1 up-regulation, prevented E-cadherin loss and tubular dedifferentiation after TGF-ß1 exposure. In addition, exogenous BMPER suppressed fibroblast activation by hindering Erk1/2 phosphorylation. Knockdown of low-density lipoprotein receptor-related protein 1 abolished the inhibitory effect of BMPER on Erk1/2 phosphorylation and fibroblast activation. Moreover, delivery of BMPER gene improved renal tubular damage and interstitial fibrosis in UUO mice. Therefore, BMPER inhibits TGF-ß1-induced tubular dedifferentiation and fibroblast activation and may hold therapeutic potential for tubulointerstitial fibrosis.

BMPER is upregulated in obesity and seems to have a role in pericardial adipose stem cells.

Pericardial adipose tissue (PAT), a visceral fat depot enveloping the heart, is an active endocrine organ and a source of free fatty acids and inflammatory cytokines. As in other fat adult tissues, PAT contains a population of adipose stem cells; however, whether these cells and/or their environment play a role in physiopathology is unknown. We analyzed several stem cell-related properties of pericardial adipose stem cells (PSCs) isolated from obese and ex-obese mice. We also performed RNA-sequencing to profile the transcriptional landscape of PSCs isolated from the different diet regimens. Finally, we tested whether these alterations impacted on the properties of cardiac mesoangioblasts isolated from the same mice. We found functional differences between PSCs depending on their source: specifically, PSCs from obese PSC (oPSC) and ex-obese PSC (dPSC) mice showed alterations in apoptosis and migratory capacity when compared with lean, control PSCs, with increased apoptosis in oPSCs and blunted migratory capacity in oPSCs and dPSCs. This was accompanied by different gene expression profiles across the cell types, where we identified some genes altered in obese conditions, such as BMP endothelial cell precursor-derived regulator (BMPER), an important regulator of BMP-related signaling pathways for endothelial cell function. The importance of BMPER in PSCs was confirmed by loss- and gain-of-function studies. Finally, we found an altered production of BMPER and some important chemokines in cardiac mesoangioblasts in obese conditions. Our findings point to BMPER as a potential new regulator of PSC function and suggest that its dysregulation could be associated with obesity and may impact on cardiac cells.

Downregulation of Hsa_circ_0000735 Inhibits the Proliferation, Migration, Invasion, and Glycolysis in Non-small-cell Lung Cancer by Targeting miR-940/BMPER Axis.

BACKGROUND: Lung cancer is the most commonly diagnosed cancer and the major cause of cancer-related deaths worldwide. The increasing studies have demonstrated that circular RNA (circRNA) was involved in the progression of various cancers, including non-small-cell lung cancer (NSCLC). This study was designed to assess the expression, roles and functional mechanisms of circ_0000735 in NSCLC. MATERIALS AND METHODS: The expression levels of circ_0000735, miR-940 and bone morphogenetic protein binding endothelial cell precursor-derived regulator (BMPER) were estimated by the real-time quantitative polymerase chain reaction (RT-qPCR). The biological behaviors of NSCLC cells such as proliferation, migration and invasion were analyzed by cell counting kit-8 (CCK-8), colony-forming assays and transwell assay, respectively. Furthermore, extracellular acid ratio and lactate production were tested to assess glycolysis levels of NSCLC cells. The interaction relationship among circ_0000735, BMPER and miR-940 was analyzed by bioinformatics database and dual-luciferase reporter assay. The protein expression level of BMPER was assessed by Western blot assay. Tumorigenesis assay was established to clarify the functional roles of circ_0000735 in vivo. RESULTS: Circ_0000735 was upregulated and significantly correlated with overall survival in patients with NSCLC. In addition, the loss-of-functional experiments revealed that knockdown of circ_0000735 repressed proliferation, migration, invasion and glycolysis of NSCLC cells and tumor growth in vivo, which was overturned by overexpression of BMPER. Similarly, overexpression of circ_0000735 enhanced proliferation, migration, invasion, and glycolysis of NSCLC cells. In addition, we also confirmed that overexpression of miR-940 impeded proliferation, migration, invasion, and glycolysis of NSCLC cells. Furthermore, overexpression of BMPER abolished si-circ_0000735 induced effects on NSCLC cells. CONCLUSION: Circ_0000735 regulated proliferation, migration, invasion, and glycolysis in NSCLC cells by targeting miR-940/BMPER axis.

Effects of BMPER, CXCL10, and HOXA9 on Neovascularization During Early-Growth Stage of Primary High-Grade Glioma and Their Corresponding MRI Biomarkers.

Neovascularization is required in high-grade glioma (HGG). The objective of this study was to explore neovascularization-related genes and their corresponding MRI biomarkers during the early-growth stage of HGG. Tumor tissues from 30 HGG patients underwent perfusion MRI scanning prior to surgery were used to establish orthotopic xenograft models, pathologically analyze the tumor vasculature and perform transcriptome sequencing. The cases were divided into two groups based on whether the xenograft was successfully established. Microvascular density and BMPER, CXCL10, and HOXA9 expression of surgical specimens in the xenograft-forming group was significantly elevated and the microvascular diameter was significantly reduced, in vitro inhibition of BMPER, CXCL10, or HOXA9 in the glioma stem cell significantly suppressed its tube formation abilities. The in vivo experiment showed that BMPER was highly expressed in the early tumor growth phase (20 days), CXCL10 and HOXA9 expression was elevated with tumor progress, and spatially associated with tumor vasculature. Perfusion weighted MRI (PWI-MRI) derived parameters, rCBV, rCBF, Ktrans, and Vp, were also increased in the xenograft-forming group. In conclusion BMPER, CXCL10, and HOXA9 promote early tumor growth and progression by stimulating neovascularization of primary HGG. The rCBV, rCBF, Ktrans, and Vp can be used as imaging biomarkers to predict the expression statuses of these genes.

Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common.

BACKGROUND: Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar to the human condition, except for being highly heritable and having a dramatically higher incidence. Here we reanalyze published genome scans of osteosarcoma in three frequently-affected dog breeds and report entirely new understandings with immediate translational indications. RESULTS: First, meta-analysis revealed association near FGF9, which has strong biological and therapeutic relevance. Secondly, risk-modeling by multiple logistic regression shows 22 of the 34 associated loci contribute to risk and eight have large effect sizes. We validated the Greyhound stepwise model in our own, independent, case-control cohort. Lastly, we updated the gene annotation from approximately 50 genes to 175, and prioritized those using cross-species genomics data. Mostly positional evidence suggests 13 genes are likely to be associated with mapped risk (including MTMR9, EWSR1 retrogene, TANGO2 and FGF9). Previous annotation included seven of those 13 and prioritized four by pathway enrichment. Ten of our 13 priority genes are in loci that contribute to risk modeling and thus can be studied epidemiologically and translationally in pet dogs. Other new candidates include MYCN, SVIL and MIR100HG. CONCLUSIONS: Polygenic osteosarcoma-risk commonly rises to Mendelian-levels in some dog breeds. This justifies caninized animal models and targeted clinical trials in pet dogs (e.g., using CDK4/6 and FGFR1/2 inhibitors).

Diaphanospondylodysostosis: Refining the prenatal diagnosis of a rare skeletal disorder.

Diaphanospondylodysostosis (DSD) is a rare autosomal recessive skeletal disorder, characterized mainly by ossification defects in vertebrae, thorax malformations, renal cystic dysplasia and usually death in the perinatal period. DSD is caused by mutations in the bone morphogenetic protein-binding endothelial regulator (BMPER) gene. We describe the prenatal findings of a non-consanguineous Jewish couple (shared Balkan origin), with three affected fetuses that presented with malformations in the spine and chest, reduced ossification of the skull and spine, horseshoe kidney and increased nuchal translucency. The unique combination of these ultrasound (US) features raised the possibility of DSD, which was confirmed by whole exome sequencing (WES) performed on a single fetal DNA and familial segregation. In the three fetuses, a novel homozygous mutation in BMPER (c.410T > A; p.Val137Asp) was found. This mutation, which segregated in the family, was not found in 65 controls of Jewish Balkan origin, and in several large databases. Taken together, the combination of a detailed prenatal US examination and WES may be highly effective in confirming the diagnosis of a rare genetic disease, in this case DSD.

BMPER Enhances Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells.

BACKGROUND/AIMS: During bone repair and remodeling, osteogenesis is coupled with angiogenesis. Bone morphogenetic protein (BMP) antagonists are important modulators of BMP signaling and bone homeostasis. Several investigations have demonstrated that one 'BMP antagonist', BMP-binding endothelial cell precursor-derived regulator (BMPER), participates in the regulation of BMP signaling. In this study, we examined the role of BMPER in the osteogenesis-angiogenesis coupling process. METHODS: Human bone mesenchymal stem cells (hBMSCs) and human umbilical vein endothelial cells (HUVECs) were used in this experiment. After overexpressing or silencing BMPER with lentiviruses or siRNA, hBMSCs were stimulated by BMP-2, and osteogenic differentiation activity was detected by alkaline phosphatase and alizarin red staining. VEGF and endostatin release were assessed by ELISA. HUVEC migration was detected by the cell scratch test and transwell migration assay, and in vitro angiogenesis was determined by the tube formation assay. Bone formation was assessed using in vivo femoral monocortical defect and ectopic bone formation models. RESULTS: BMP-2 upregulated BMPER expression. Overexpression of BMPER remarkably enhanced BMP-2-induced osteogenic differentiation, while suppression of BMPER effectively inhibited this process both in vitro and in vivo. In addition, overexpression of BMPER promoted BMP-2-induced VEGF expression in vitro and vascularization in the ectopic bone formation model. CONCLUSION: BMPER functions as a positive regulator of the osteogenesis-angiogenesis coupling process in hBMSCs, suggesting a novel therapeutic role of BMPER in the regenerative capacity of bone repair.

Prenatal diagnosis of diaphanospondylodysostosis (DSD): a case report.

We present a case of diaphanospondylodysostosis (DSD) which showed increased nuchal translucency at 1st trimester and missing ossification of the lower spine, short ribs with posterior gaps, and absent nasal bone in midtrimester. Autopsy revealed additionally bilateral nephroblastomatosis. Molecular genetic analysis showed a new mutation in the BMPER gene.