Assessing the contribution of genes involved in monogenic bone disorders to the etiology of atypical femoral fractures.

BACKGROUND: Recent studies suggested that genetic variants associated with monogenic bone disorders were involved in the pathogenesis of atypical femoral fractures (AFF). Here, we aim to identify rare genetic variants by whole exome sequencing in genes involved in monogenic rare skeletal diseases in 12 women with AFF and 4 controls without any fracture. RESULTS: Out of 33 genetic variants identified in women with AFF, eleven (33.3%) were found in genes belonging to the Wnt pathway (LRP5, LRP6, DAAM2, WNT1, and WNT3A). One of them was rated as pathogenic (p.Pro582His in DAAM2), while all others were rated as variants of uncertain significance according to ClinVar and ACMG criteria. CONCLUSIONS: Osteoporosis, rare bone diseases, and AFFs may share the same genes, thus making it even more difficult to identify unique risk factors.

Atorvastatin exerts a preventive effect against steroid-induced necrosis of the femoral head by modulating Wnt5a release.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings.

Role of LRP5/6/GSK-3ß/ß-catenin in the differences in exenatide- and insulin-promoted T2D osteogenesis and osteomodulation.

BACKGROUND AND PURPOSE: Insulin and exenatide are two hypoglycaemic agents that exhibit different osteogenic effects. This study compared the differences between exenatide and insulin in osseointegration in a rat model of Type 2 diabetes (T2D) and explored the mechanisms promoting osteogenesis in this model of T2D. EXPERIMENTAL APPROACH: In vivo, micro-CT was used to detect differences in the peri-implant bone microstructure in vivo. Histology, dual-fluorescent labelling, immunofluorescence and immunohistochemistry were used to detect differences in tissue, cell and protein expression around the implants. In vitro, RT-PCR and western blotting were used to measure the expression of osteogenesis- and Wnt signalling-related genes and proteins in bone marrow mesenchymal stromal cells (BMSCs) from rats with T2D (TBMSCs) after PBS, insulin and exenatide treatment. RT-PCR was used to detect the expression of Wnt bypass cascade reactions under Wnt inactivation. KEY RESULTS: Micro-CT and section staining showed exenatide extensively promoted peri-implant osseointegration. Both in vivo and in vitro experiments showed exenatide substantially increased the expression of osteogenesis-related and activated the LRP5/6/GSK-3ß/ß-catenin-related Wnt pathway. Furthermore, exenatide suppressed expression of Bmpr1a to inhibit lipogenesis and promoted expression of Btrc to suppress inflammation. CONCLUSION AND IMPLICATIONS: Compared to insulin, exenatide significantly improved osteogenesis in T2D rats and TBMSCs. In addition to its dependence on LRP5/6/GSK-3ß/ß-catenin signalling for osteogenic differentiation, exenatide-mediated osteomodulation also involves inhibition of inflammation and adipogenesis by BMPR1A and ß-TrCP, respectively.

Coats-Like Presentation of Familial Exudative Vitreoretinopathy Associated With a Novel LRP5 Variant.

This report describes a unique case of a Coats-like presentation of familial exudative vitreoretinopathy in an 11-year-old girl. The patient was originally referred for evaluation of presumed Coats disease and presented with telangiectatic vessels, perivascular exudates, diffuse peripheral exudation, and intraretinal hemorrhages. Clinical and angiographical findings were consistent with familial exudative vitreoretinopathy, while genetic testing identified variants of uncertain significance in two associated genes, LRP5 and ZNF408. In silico analysis predicts the LRP5 variant to be pathogenic. Retinal vasculopathies often have phenotypic overlap, warranting angiographic examination of both eyes and genetic testing to uncover the correct diagnosis and guide proper treatment. [Ophthalmic Surg Lasers Imaging Retina 2024;55:462-466.].

Hydrolyzed egg yolk peptide prevented osteoporosis by regulating Wnt/ß-catenin signaling pathway in ovariectomized rats.

Hydrolyzed egg yolk peptide (YPEP) was shown to increase bone mineral density in ovariectomized rats. However, the underlying mechanism of YPEP on osteoporosis has not been explored. Recent studies have shown that Wnt/ß-catenin signaling pathway and gut microbiota may be involved in the regulation of bone metabolism and the progression of osteoporosis. The present study aimed to explore the preventive effect of the YPEP supplementation on osteoporosis in ovariectomized (OVX) rats and to verify whether YPEP can improve osteoporosis by regulating Wnt/ß-catenin signaling pathway and gut microbiota. The experiment included five groups: sham surgery group (SHAM), ovariectomy group (OVX), 17-ß estradiol group (E2: 25 µg /kg/d 17ß-estradiol), OVX with low-dose YPEP group (LYPEP: 10 mg /kg/d YPEP) and OVX with high-dose YPEP group (HYPEP: 40 mg /kg/d YPEP). In this study, all the bone samples used were femurs. Micro-CT analysis revealed improvements in both bone mineral density (BMD) and microstructure by YPEP treatment. The three-point mechanical bending test indicated an enhancement in the biomechanical properties of the YPEP groups. The serum levels of bone alkaline phosphatase (BALP), bone gla protein (BGP), calcium (Ca), and phosphorus (P) were markedly higher in the YPEP groups than in the OVX group. The LYPEP group had markedly lower levels of alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) and C-terminal telopeptide of type I collagen (CTX-I) than the OVX group. The YPEP groups had significantly higher protein levels of the Wnt3a, ß-catenin, LRP5, RUNX2 and OPG of the Wnt/ß-catenin signaling pathway compared with the OVX group. Compared to the OVX group, the ratio of OPG/RANKL was markedly higher in the LYPEP group. At the genus level, there was a significantly increase in relative abundance of Lachnospiraceae_NK4A136_group and a decrease in Escherichia_Shigella in YPEP groups, compared with the OVX group. However, in the correlation analysis, there was no correlation between these two bacteria and bone metabolism and microstructure indexes. These findings demonstrate that YPEP has the potential to improve osteoporosis, and the mechanism may be associated with its modulating effect on Wnt/ß-catenin signaling pathway.

Low-density lipoprotein receptor-related protein 5/6 promotes endometrial cancer progression and cancer cell immune escape.

The study investigated the potential association of the low-density lipoprotein (LDL) genome with endometrial cancer progression based on the Gene Expression Omnibus data set and The Cancer Genome Atlas data set. Differential and weighted gene coexpression network analysis was performed on endometrial cancer transcriptome datasets GSE9750 and GSE106191. The protein-protein interaction network was built using LDL-receptor proteins and the top 50 tumor-associated genes. Low-density lipoprotein-related receptors 5/6 (LRP5/6) in endometrial cancer tissues were correlated with oncogenes, cell cycle-related genes, and immunological checkpoints using Spearman correlation. MethPrimer predicted the LRP5/6 promoter CpG island. LRP2, LRP6, LRP8, LRP12, low-density lipoprotein receptor-related protein-associated protein, and LRP5 were major LDL-receptor-related genes associated with endometrial cancer. LRP5/6 was enriched in various cancer-related pathways and may be a key LDL-receptor-related gene in cancer progression. LRP5/6 may be involved in the proliferation process of endometrial cancer cells by promoting the expression of cell cycle-related genes. LRP5/6 may be involved in the proliferation of endometrial cancer cells by promoting the expression of cell cycle-related genes. LRP5/6 may promote the immune escape of cancer cells by promoting the expression of immune checkpoints, promoting endometrial cancer progression. The MethPrimer database predicted that the LRP5/6 promoter region contained many CpG islands, suggesting that DNA methylation can occur in the LRP5/6 promoter region. LRP5/6 may aggravate endometrial cancer by activating the phosphoinositide 3-kinase/protein kinase B pathway.

Relationship between polymorphisms and mutations at rs7125942 and rs3736228 of LRP5 gene and bone metabolism in postmenopausal women.

OBJECTIVE: To analyze the relationship between the polymorphism and mutation of rs7125942 and rs3736228 locus in the low-density lipoprotein receptor-related protein 5 (LRP5) genotype and bone mineral density (BMD) in postmenopausal women in Xinjiang, China, to provide a basis for prevention and treatment of the disease. METHODS: According to the results of dual-energy X-ray (DEXA) determination of BMD, the 136 subjects were divided into three groups: Group A: normal bone mass, Group B: osteopenia, Group C: osteoporosis. 1. Age, body, mass index (BMI), and menopause of all subjects were recorded. 2. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and clinical biochemical data were determined. 3. LRP5 locus polymorphisms were determined by time-of-flight mass spectrometry. RESULTS: 1. Compared with group A, the age, ALP, Cr, and BUN levels in group B and group C were increased, but UA levels were lower (P < 0.05), and Serum P was higher in the group C (P < 0.05). 2. There was no statistically significant difference in the prevalence of diabetes between the three groups (P > 0.05). 3. The ROC curves for different BMD sites such as L1, L2, L3, L4, L total, and femoral neck were 0.929, 0.955, 0.901, 0.914, 0.885, and 0.873 (P < 0.01). 4. At rs7125942 locus, there was statistically significant difference in the distribution of wild-type (CC) and mutant (CG) with the normal bone mass (NBM) group and the abnormal bone mass (ABM) group (P < 0.05). 5. At rs7125942 locus, compared with wild-type (CC), mutant (CG) had lower LDL and FPG in NBM group (P < 0.05), and lower serum ALP in the ABM group (P < 0.05). At rs3736228 locus, the BMD (Femoral neck) of mutant (CT/TT) was lower than that of wild-type (CC) in the NBM group (P < 0.05). 6. Age and menopausal years were negatively correlated with BMD of the femoral neck and L1-4 (P < 0.05), and BMI and TG were positively (P < 0.05), and the results of multiple linear regression analysis showed that age, BMI, and TG were both independent factors affecting BMD (P < 0.05).

MAGP2 promotes osteogenic differentiation during fracture healing through its crosstalk with the ß-catenin pathway.

Osteogenic differentiation is important for fracture healing. Microfibrial-associated glycoprotein 2 (MAGP2) is found to function as a proangiogenic regulator in bone formation; however, its role in osteogenic differentiation during bone repair is not clear. Here, a mouse model of critical-sized femur fracture was constructed, and the adenovirus expressing MAGP2 was delivered into the fracture site. Mice with MAGP2 overexpression exhibited increased bone mineral density and bone volume fraction (BV/TV) at Day 14 postfracture. Within 7 days postfracture, overexpression of MAGP2 increased collagen I and II expression at the fracture callus, with increasing chondrogenesis. MAGP2 inhibited collagen II level but elevated collagen I by 14 days following fracture, accompanied by increased endochondral bone formation. In mouse osteoblast precursor MC3T3-E1 cells, MAGP2 treatment elevated the expression of osteoblastic factors (osterix, BGLAP and collagen I) and enhanced ALP activity and mineralization through activating ß-catenin signaling after osteogenic induction. Besides, MAGP2 could interact with lipoprotein receptor-related protein 5 (LRP5) and upregulated its expression. Promotion of osteogenic differentiation and ß-catenin activation mediated by MAGP2 was partially reversed by LRP5 knockdown. Interestingly, ß-catenin/transcription factor 4 (TCF4) increased MAGP2 expression probably by binding to MAGP2 promoter. These findings suggest that MAGP2 may interact with ß-catenin/TCF4 to enhance ß-catenin/TCF4's function and activate LRP5-activated ß-catenin signaling pathway, thus promoting osteogenic differentiation for fracture repair. mRNA sequencing identified the potential targets of MAGP2, providing novel insights into MAGP2 function and the directions for future research.

LRP5 competes for SPOP binding to enhance tumorigenesis mediated by Daxx and PD-L1 in prostate cancer.

Genetic factors coordinate with environmental factors to drive the pathogenesis of prostate adenocarcinoma (PRAD). SPOP is one of the most mutated genes and LRP5 mediates lipid metabolism that is abnormally altered in PRAD. Here, we investigated the potential cross-talk between SPOP and LRP5 in PRAD. We find a negative correlation between SPOP and LRP5 proteins in PRAD. SPOP knockdown increased LRP5 protein while SPOP overexpression resulted in LRP5 reduction that was fully rescued by proteasome inhibitors. LRP5 intracellular tail has SPOP binding site and the direct interaction between LRP5 and SPOP was confirmed by Co-IP and GST-pulldown. Moreover, LRP5 competed with Daxx for SPOP-mediated degradation, establishing a dynamic balance among SPOP, LRP5 and Daxx. Overexpression of LRP5 tail could shift this balance to enhance Daxx-mediated transcriptional inhibition, and inhibit T cell activity in a co-culture system. Further, we generated human and mouse prostate cancer cell lines expressing SPOP variants (F133V, A227V, R368H). SPOP-F133V and SPOP-A227V have specific effects in up-regulating the protein levels of PD-1 and PD-L1. Consistently, SPOP-F133V and SPOP-A227V show robust inhibitory effects on T cells compared to WT SPOP in co-culture. This is further supported by the mouse syngeneic model showing that SPOP-F133V and SPOP-A227V enhance tumorigenesis of prostate cancer in in-vivo condition. Taken together, our study provides evidence that SPOP-LRP5 crosstalk plays an essential role, and the genetic variants of SPOP differentially modulate the expression and activity of immune checkpoints in prostate cancer.

Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function.

AIMS: There is little information on the regulation of cholesterol homeostasis in the brain. Whether cholesterol crosses the blood-brain barrier is under investigation, but the present understanding is that cholesterol metabolism in the brain is independent from that in peripheral tissues. Lipoprotein receptors from the LDL receptor family (LRPs) have key roles in lipid particle accumulation in cells involved in vascular and cardiac pathophysiology; however, their function on neural cells is unknown. METHODS AND RESULTS: The expression of LRP5 and the components and targets of its downstream signalling pathway, the canonical Wnt pathway, including ß-catenin, LEF1, VEGF, OPN, MMP7, and ADAM10, is analysed in the brains of Wt and Lrp5-/- mice and in a neuroblastoma cell line. LRP5 expression is increased in a time- and dose-dependent manner after lipid loading in neuronal cells; however, it does not participate in cholesterol homeostasis as shown by intracellular lipid accumulation analyses. Neurons challenged with staurosporin and H2O2 display an anti-apoptotic protective role for LRP5. CONCLUSIONS: For the first time, it has been shown that neurons can accumulate intracellular lipids and lipid uptake is performed mainly by the LDLR, while CD36, LRP1, and LRP5 do not play a major role. In addition, it has been shown that LRP5 triggers the canonical Wnt pathway in neuronal cells to generate pro-survival signals. Finally, Lrp5-/- mice have maintained expression of LRP5 only in the brain supporting the biological plausible concept of the need of brain LRP5 to elicit pro-survival processes and embryonic viability.

Genetic detection of two novel LRP5 pathogenic variants in patients with familial exudative vitreoretinopathy.

BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation. METHODS: Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease. RESULTS: A 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein. CONCLUSIONS: Two novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.

LRP5, SLC6A3, and SOX10 Expression in Conventional Ameloblastoma.

Cell proliferation and invasion are characteristic of many tumors, including ameloblastoma, and are important features to target in possible future therapeutic applications. OBJECTIVE: The objective of this study was the identification of key genes and inhibitory drugs related to the cell proliferation and invasion of ameloblastoma using bioinformatic analysis. METHODS: The H10KA_07_38 gene profile database was analyzed by Rstudio and ShinyGO Gene Ontology enrichment. String, Cytoscape-MCODE, and Kaplan-Meier plots were generated, which were subsequently validated by RT-qPCR relative expression and immunoexpression analyses. To propose specific inhibitory drugs, a bioinformatic search using Drug Gene Budger and DrugBank was performed. RESULTS: A total of 204 significantly upregulated genes were identified. Gene ontology enrichment analysis identified four pathways related to cell proliferation and cell invasion. A total of 37 genes were involved in these pathways, and 11 genes showed an MCODE score of ≥0.4; however, only SLC6A3, SOX10, and LRP5 were negatively associated with overall survival (HR = 1.49 (p = 0.0072), HR = 1.55 (p = 0.0018), and HR = 1.38 (p = 0.025), respectively). The RT-qPCR results confirmed the significant differences in expression, with overexpression of >2 for SLC6A3 and SOX10. The immunoexpression analysis indicated positive LRP5 and SLC6A3 expression. The inhibitory drugs bioinformatically obtained for the above three genes were parthenolide and vorinostat. CONCLUSIONS: We identify LRP5, SLC6A3, and SOX10 as potentially important genes related to cell proliferation and invasion in the pathogenesis of ameloblastomas, along with both parthenolide and vorinostat as inhibitory drugs that could be further investigated for the development of novel therapeutic approaches against ameloblastoma.

The selenoprotein P-LRP5/6-WNT3A complex promotes tumorigenesis in sporadic colorectal cancer.

Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique selenocysteine-containing protein, to sporadic colorectal carcinogenesis challenges this paradigm. SELENOP is predominately secreted by the liver but is also expressed in various cells of the small intestine and colon in mice and humans. In this issue of the JCI, Pilat et al. demonstrate that increased SELENOP expression promoted the progression of conventional adenomas to carcinoma. SELENOP functioned as a modulator of canonical WNT signaling activity through interactions with WNT3A and its coreceptor LDL receptor-related protein 5/6 (LRP5/6). Secreted SELENOP formed a concentration gradient along the gut crypt axis, which might amplify WNT signaling activity by binding to LRPL5/6. The mechanism for WNT control via SELENOP may affect colorectal tumorigenesis and provide therapeutic targets for CRC.

Medical Care Use Among Patients with Monogenic Osteoporosis Due to Rare Variants in LRP5, PLS3, or WNT1.

Pathogenic variants in the LRP5, PLS3, or WNT1 genes can significantly affect bone mineral density, causing monogenic osteoporosis. Much remains to be discovered about the phenotype and medical care needs of these patients. The purpose of this study was to examine the use of medical care among Dutch individuals identified between 2014 and 2021 with a pathogenic or suspicious rare variant in LRP5, PLS3, or WNT1. In addition, the aim was to compare their medical care utilization to both the overall Dutch population and the Dutch Osteogenesis Imperfecta (OI) population. The Amsterdam UMC Genome Database was used to match 92 patients with the Statistics Netherlands (CBS) cohort. Patients were categorized based on their harbored variants: LRP5, PLS3, or WNT1. Hospital admissions, outpatient visits, medication data, and diagnosis treatment combinations (DTCs) were compared between the variant groups and, when possible, to the total population and OI population. Compared to the total population, patients with an LRP5, PLS3, or WNT1 variant had 1.63 times more hospital admissions, 2.0 times more opened DTCs, and a greater proportion using medication. Compared to OI patients, they had 0.62 times fewer admissions. Dutch patients with an LRP5, PLS3, or WNT1 variant appear to require on average more medical care than the total population. As expected, they made higher use of care at the surgical and orthopedic departments. Additionally, they used more care at the audiological centers and the otorhinolaryngology (ENT) department, suggesting a higher risk of hearing-related problems.

LRP5-/6 gene polymorphisms and its association with risk of abnormal bone mass in postmenopausal women.

OBJECTIVES: To assess LRP5-/6 gene polymorphisms and its association with risk of abnormal bone mass (ABM) in postmenopausal women. METHODS: The study recruited 166 patients with ABM (case group) and 106 patients with normal bone mass (control group) based on bone mineral density (BMD) results. Multi-factor dimensionality reduction (MDR) was used to analyze the interaction between the Low-density lipoprotein receptor-related protein 5 (LRP5) gene (rs41494349, rs2306862) and the Low-density lipoprotein receptor-related protein 6 (LRP6) gene (rs10743980, rs2302685) and the subjects' clinical characteristics of age and menopausal years. RESULTS: (1) Logistic regression analysis showed that the subjects with the CT or TT genotype at rs2306862 had a higher risk of ABM than those with the CC genotype (OR = 2.353, 95%CI = 1.039-6.186; OR = 2.434, 95%CI = 1.071, 5.531; P < 0.05). The subjects with the TC genotype at rs2302685 had a higher risk of ABM than those with the TT genotype (OR = 2.951, 95%CI = 1.030-8.457, P < 0.05). (2) When taking the three Single-nucleotide polymorphisms (SNPs) together, the accuracy was the highest with the cross-validation consistency of 10/10 (OR = 1.504, 95%CI:1.092-2.073, P < 0.05), indicating that the LRP5 rs41494349 and LRP6 rs10743980, rs2302685 were interactively associated with the risk of ABM. (3) Linkage disequilibrium (LD) results revealed that the LRP5 (rs41494349,rs2306862) were in strong LD (D' > 0.9, r2 > 0.3). AC and AT haplotypes were significantly more frequently distributed in the ABM group than in the control group, indicating that subjects carrying the AC and AT haplotypes were associated with an increased risk of ABM (P < 0.01). (4) MDR showed that rs41494349 & rs2302685 & rs10743980 & age were the best model for ABM prediction. The risk of ABM in "high-risk combination" was 1.00 times that of "low-risk combination"(OR = 1.005, 95%CI: 1.002-1.008, P < 0.05). (5) MDR showed that there was no significant association between any of the SNPs and menopausal years and ABM susceptibility. CONCLUSION: These findings indicate that LRP5-rs2306862 and LRP6-rs2302685 polymorphisms and gene-gene and gene-age interactions may increase the risk of ABM in postmenopausal women. There was no significant association between any of the SNPs and menopausal years and ABM susceptibility.

SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions.

Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP's contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.

Got WNTS? Insight into bone health from a WNT perspective.

WNT signaling, essential for many aspects of development, is among the most commonly altered pathways associated with human disease. While initially studied in cancer, dysregulation of WNT signaling has been determined to be essential for skeletal development and the maintenance of bone health throughout life. In this review, we discuss the role of Wnt signaling in bone development and disease with a particular focus on two areas. First, we discuss the roles of WNT signaling pathways in skeletal development, with an emphasis on congenital and idiopathic skeletal syndromes and diseases that are associated with genetic variations in WNT signaling components. Next, we cover a topic that has long been an interest of our laboratory, how high and low levels of WNT signaling affects the establishment and maintenance of healthy bone mass. We conclude with a discussion of the status of WNT-based therapeutics in the treatment of skeletal disease.

Paternal sleep deprivation induces metabolic perturbations in male offspring via altered LRP5 DNA methylation of pancreatic islets.

Diabetes and metabolic perturbation are global health challenges. Sleep insufficiency may trigger metabolic dysregulation leading to diabetes. However, the intergenerational transmission of this environmental information is not clearly understood. The research objective was to determine the possible effect of paternal sleep deprivation on the metabolic phenotype of the offspring and to investigate the underlying mechanism of epigenetic inheritance. Male offspring of sleep-deprived fathers exhibit glucose intolerance, insulin resistance, and impaired insulin secretion. In these SD-F1 offspring, a reduction in beta cell mass and proliferation of beta cells were observed. Mechanistically, in pancreatic islets of SD-F1 offspring, we identified alterations in DNA methylation at the promoter region of the LRP5 (LDL receptor related protein 5) gene, a coreceptor of Wnt signaling, resulting in downregulation of downstream effectors cyclin D1, cyclin D2, and Ctnnb1. Restoration of Lrp5 in the pancreas of SD-F1 male mice could improve impaired glucose tolerance and expression of cyclin D1, cyclin D2, and Ctnnb1. This study might significantly contribute to our understanding of the effects of sleeplessness on health and metabolic disease risk from the perspective of the heritable epigenome.

Overexpressions of RHOA, CSNK1A1, DVL2, FZD8, and LRP5 genes enhance gastric cancer development in the presence of Helicobacter pylori.

BACKGROUND AND STUDY AIMS: Intestinal metaplasia (IM), and Helicobacter pylori (HP) infection can be shown as risk factors in the development of gastric cancer (GC). WNT signaling pathway plays a critical role in carcinogenesis. However, the literature studies are limited on the significance of this pathway for the transition from IM to GC. PATIENTS AND METHODS: We aimed to investigate the importance of the genes of WNT signaling pathways diagnostic and prognostic markers in the presence and absence of HP in conversion from IM to GC. 104 patients, (GC group n = 35, IM group n = 45, control group n = 25) were included in this case-control study. Expression of genes in WNT signalling were searched in study groups with qRT-PCR array and qRT-PCR method. Data were analysed using PCR array data analysis software. RESULTS: Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was detected in the GC and IM groups compared to the control group (p < 0.05). Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was observed in patients with metastatic GC compared to patients with GC without metastasis (p < 0.05). It was found that the RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes were statistically significantly over-expressed in diffuse GC patients compared to non-diffuse GC patients (p < 0.05). Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was detected in HP positive IM patients compared to HP negative IM patients (p < 0.05). CONCLUSION: Overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes in IM may suggest that these genes are important markers in the development of IM and inflammation with HP. In addition, these genes are linked to tumor burden in the GC group. Consequently, we can conclude that these genes are poor prognosis biomarkers for GC and have the potential to be used as markers for future treatment monitoring.