BMP Signaling Pathway Research Articles

Suppression of chemically induced mammary cancer by early-life oral administration of cholera toxin in mice is associated with aberrant regulation of Bmp and Notch signaling pathways.

Lately, significant attention has been drawn towards the potential efficacy of cholera toxin (CT)-an exotoxin produced by the small intestine pathogenic bacterium Vibrio cholera-in modulating cancer-promoting events. In a recent study, we demonstrated that early-life oral administration of non-pathogenic doses of CT in mice suppressed chemically-induced carcinogenesis in tissues distantly located from the gut. In the mammary gland, CT pretreatment was shown to reduce tumor multiplicity, increase apoptosis and alter the expression of several cancer-related molecules. In the present work we investigated the protumorigenic mammary microenvironment for possible associations between early life CT administration and the expression of key components of the Bmp and Notch signaling pathways. Total RNA from mammary tissue samples were retrieved from a recent experiment where FVB/N female mice were preconditioned with CT and later treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA). Real-time PCR was used for relative quantification of gene expression. Our results revealed that CT anti-tumor effects significantly correlated with deregulation of crucial BMP pathway elements, with downregulation of Bmp7 ligand and upregulation of inhibitory Smad6 being the most prominent alterations observed. Concerning Notch signaling pathway, significantly elevated gene expression levels in the CT-treated DMBA mice, as compared to their non-treated counterparts, were also identified at the ligand-receptor level. These findings suggest that CT tumor protective effects in the mammary gland are associated with discerning deregulation of components of both Bmp and Notch signaling pathways and provide insights into the mechanisms underlying CT's anti-cancer outcome.

The BMP Signaling Pathway: Bridging Maternal-Fetal Crosstalk in Early Pregnancy.

The maintenance of early pregnancy is a complex and distinctive process, primarily characterized by critical reproductive events such as embryo implantation, trophoblasts differentiation, decidualization, and extravillous trophoblasts (EVTs) invasion etc. However, dysregulation of these essential reproductive processes can result in various pregnancycomplications, including recurrent miscarriage, preeclampsia, and fetal growth restriction etc. Notably, these complications exhibit an interconnected regulatory network that suggests shared underlying pathophysiological mechanisms. Meanwhile, the role of the BMP signaling pathway in sustaining early pregnancy is increasingly being investigated and elucidated. In this review, we have clarified the specific molecular mechanisms which are fundamental to essential reproductive processes and summarize an overview of animal models associated with BMP signaling molecules. In addition, we present a novel perspective on several contentious viewpoints regarding the functional roles of BMP ligands. Therefore, we anticipated a comprehensive understanding of the precise ways in which the BMP signaling pathway affects reproductive events during early pregnancy could provide new perspectives and approaches for preventing and addressing early pregnancy complications.

Meta-analysis of retinal transcriptome profiling studies in animal models of myopia

ObjectiveMyopia prevalence is increasing at alarming rates, yet the underlying mechanistic causes are not understood. Several studies have employed experimental animal models of myopia and transcriptome profiling to identify genes and pathways contributing to myopia. In this study, we determined the retinal transcriptome changes in response to form deprivation in mouse retinas. We then conducted a transcriptome meta-analysis incorporating all publicly available datasets and analyzed how the results related to the genes associated with refractive errors in human genome-wide association studies (GWAS).MethodsForm deprivation was induced in three male C57BL6/J mice from postnatal day 28 (P28) to P42. Retinal gene expression was analyzed with RNA sequencing, followed by differential gene expression analysis with DESeq2 and identification of associated pathways with the Kyoto Encyclopedia of Genes and Genomes (KEGG). A systematic search identified four similar retinal transcriptomics datasets in response to experimental myopia using chicks or mice. The five studies underwent transcriptome meta-analyses to determine retinal gene expression changes and associated pathways. The results were compared with genes associated with human myopia.ResultsDifferential gene expression analysis of form-deprived mouse retinas revealed 235 significantly altered transcripts, implicating the BMP2 signaling pathway and circadian rhythms, among others. Transcriptome-wide meta-analyses of experimental myopia datasets found 427 differentially expressed genes in the mouse model and 1,110 in the chick model, with limited gene overlap between species. Pathway analysis of these two gene sets implicated TGF-beta signaling and circadian rhythm pathways in both mouse and chick retinas. Some pathways associated only with mouse retinal changes included dopamine signaling and HIF-1 signaling pathway, whereas glucagon signaling was only associated with gene changes in chick retinas. The follistatin gene changed in both mouse and chick retinas and has also been implicated in human myopia. TGF-beta signaling pathway and circadian entrainment processes were associated with myopia in mice, chicks, and humans.ConclusionThis study highlights the power of combining datasets to enhance statistical power and identify robust gene expression changes across different experimental animal models and conditions. The data supports other experimental evidence that TGF-beta signaling pathway and circadian rhythms are involved in myopic eye growth.

Hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway. Up to 90% of disease-causal variants are observed in ENG and ACVRL1, with SMAD4 and GDF2 less frequently responsible for HHT. In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases. Arteriovenous malformations (AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through pulmonary AVMs (causingischaemic stroke or cerebral abscess) and left-to-right through systemic AVMs(causing high cardiac output). Children usually experience isolated epistaxis; in rare cases, childhoodcomplications occur from large AVMs in the lungs or central nervous system. Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members. Novel therapeutics, such as systemic antiangiogenic therapies, are actively being investigated. Although HHT is associated with increased morbidity, the appropriate screening and treatment of visceral AVMs, and the effective management of bleeding and anaemia, improves quality of life and overall survival.

Ligand-Independent Vitamin D Receptor Actions Essential for Keratinocyte Homeostasis in the Skin.

Recently, we demonstrated that the alopecia observed in vitamin D receptor gene-deficient (Vdr-KO) rats is not seen in rats with a mutant VDR(R270L/H301Q), which lacks ligand-binding ability, suggesting that the ligand-independent action of VDR plays a crucial role in maintaining the hair cycle. Since Vdr-KO rats also showed abnormalities in the skin, the relationship between alopecia and skin abnormalities was examined. To clarify the mechanism of actions of vitamin D and VDR in the skin, protein composition, and gene expression patterns in the skin were compared among Vdr-KO, Vdr-R270L/H301Q, and wild-type (WT) rats. While Vdr-R270L/H301Q rats exhibited normal skin formation similar to WT rats, Vdr-KO rats showed remarkable hyperkeratosis and trans-epidermal water loss in the skin. RNA sequencing and proteomic analysis revealed that the gene and protein expression patterns in Vdr-KO rats significantly differed from those in WT and Vdr-R270L/H301Q rats, with a marked decrease in the expression of factors involved in Shh, Wnt, and Bmp signaling pathways, a dramatic reduction in the expression of hair keratins, and a substantial increase in the expression of epidermal keratins. This study clearly demonstrated that non-liganded VDR is significantly involved in the differentiation, proliferation, and cell death of keratinocytes in hair follicles and the epidermis.

Alternative splicing of EZH2 regulated by SNRPB mediates hepatocellular carcinoma progression via BMP2 signaling pathway.

Increasing evidence suggests that aberrant alternative splicing plays crucial roles in tumorigenesis. However, the function of EZH2 splice variants as well as the mechanism by which EZH2 alternative splicing occurs in hepatocellular carcinoma (HCC) remain elusive. Here, we analyzed both our own and published transcriptomic data, obtaining 19 splice variants of EZH2 in addition to canonical full-length EZH2-A in HCC. We found that expression of EZH2-A/EZH2-B in tumor tissues and cell lines was significantly higher than in normal tissues. Conversely, EZH2-C expression was lower in tumor tissues and cell lines than in normal tissues. Further functional analysis indicated that unlike full-length EZH2-A that promotes H3K27 methylation, EZH2-C reduced H3K27me3 levels. EZH2-C inhibited proliferation, migration, invasion of HCC cells. Moreover, EZH2-A and EZH2-C regulate the BMP2 signaling pathway oppositely. Mechanistically, EZH2's alternative splicing was mediated by splicing factor SNRPB. In summary, this study revealed that alternative splicing of EZH2 regulates HCC.

Ethanol induces craniofacial defects in Bmp mutants independent of nkx2.3 by elevating cranial neural crest cell apoptosis.

Fetal Alcohol Spectrum Disorders (FASD) describes a wide range of neurological defects and craniofacial malformations associated with prenatal ethanol exposure. While there is growing evidence for a genetic component to FASD, little is known of the cellular mechanisms underlying these ethanol-sensitive loci in facial development. Endoderm morphogenesis to form lateral protrusions called pouches is one key mechanism in facial development. We have previously shown that multiple members of the Bone Morphogenetic Pathway (Bmp) signaling pathway, a key regulator of pouch formation, interacts with ethanol disrupting facial development. However, ethanol does not directly impact Bmp signaling suggesting that downstream effectors, like nkx2.3 may mediate the impact of ethanol on Bmp mutants. Here we use an ethanol exposure paradigm with nkx2.3 knockdown approaches to test if loss of nkx2.3 sensitizes Bmp mutants to ethanol induced facial defects. We then combine a morphometric approach with Hybridization Chain Reaction and immunofluorescence to examine the cellular mechanisms underlying Bmp-ethanol interactions. We show that Bmp-ethanol interactions alter morphology of the endodermal pouches, independent of nkx2.3 gene expression. Morpholino knock down of nkx2.3 does not sensitize wild type or bmp4 mutant larvae to ethanol-induced facial defects. However, we did observe a significant increase CNCC apoptosis in ethanol-treated Bmp mutants. Collectively, our results suggest that ethanol's mode of action is independent of downstream Bmp effectors, converging on CNCC cell survival. Ultimately, our work provides a mechanistic paradigm of ethanol-induced facial defects and connects ethanol exposure with concrete cellular events.

Polycomb protein Bmi1 promotes odontoblast differentiation by accelerating Wnt and BMP signaling pathways.

Bmi1 is a polycomb protein localized in stem cells and maintains their stemness. This protein is also reported to regulate the expression of various differentiation genes. In this study, to analyze the role of Bmi1 during dentinogenesis, we examined the immunohistochemical localization of Bmi1 during rat tooth development as well as after cavity preparation. Bmi1 localization was hardly detected in the dental mesenchyme at the bud and cap stages. After the bell stage, however, this protein became detectable in preodontoblasts and early odontoblasts just beginning dentin matrix secretion. As dentin formation progressed, Bmi1 immunoreactivity in the odontoblasts decreased in intensity. After cavity preparation, cells lining the dentin and some pulp cells under the cavity were immunopositive for Bmi1 at 4days. Odontoblast-like cells forming reparative dentin were immunopositive for Bmi1 at 1week, whereas their immunoreactivity was not detected after 8weeks. We further analyzed the function of Bmi1 using KN-3 cells, a dental mesenchymal cell line. Overexpression of Bmi1 in KN-3 cells promoted mineralized tissue formation. In contrast, siRNA knockdown of Bmi1 in KN-3 cells reduced alkaline phosphatase activity and the expression of odontoblast differentiation marker genes such as Runx2, osterix, and osteocalcin. Additionally, KN-3 cells transfected with siRNA against Bmi1 showed reduced nuclear transition of β-catenin and expression of phosphorylated-Smad1/5/8. Taken together, these findings suggest that Bmi1 was localized in the odontoblast-lineage cells in their early differentiation stages. Bmi1 might positively regulate their differentiation by accelerating Wnt and BMP signaling pathways.

Breast Cancer Subtype-Specific Organotropism is Dictated by FOXF2-Regulated Metastatic Dormancy and Recovery.

Breast cancer subtypes display different metastatic organotropism. Identification of the mechanisms underlying subtype-specific organotropism could help uncover potential approaches to prevent and treat metastasis. Herein, we found that FOXF2 promoted the seeding and proliferative recovery from dormancy of luminal breast cancer (LumBC) and basal-like breast cancer (BLBC) cells in the bone by activating the NF-κB and BMP signaling pathways. Conversely, FOXF2 suppressed the seeding and proliferative recovery of BLBC cells in the lung by repressing the TGF-β signaling pathway. FOXF2 directly upregulated RelA/p65 transcription and expression in LumBC and BLBC cells by binding to the RELA proximal promoter region, and RelA/p65 bound to the FOXF2 proximal promoter region to upregulate expression, forming a positive feedback loop. Targeting the NF-κB pathway efficiently prevented the metastasis of FOXF2-overexpressing breast cancer cells to the bone, while inhibiting TGF-β signaling blocked the metastasis of BLBC with low FOXF2 expression to the lung. These findings uncover critical mechanisms of breast cancer subtype-specific organotropism and provide insight into precision assessment and treatment strategies.

A genome-engineered tool set for Drosophila TGF-β/BMP signaling studies.

Ligands of the TGF-β/BMP superfamily are crucially involved in the regulation of growth, patterning and organogenesis and can act as long-range morphogens. Essential for understanding TGF-β/BMP signaling dynamics and regulation are tools that allow monitoring and manipulating pathway components at physiological expression levels and endogenous spatiotemporal patterns. We used genome engineering to generate a comprehensive library of endogenously epitope- or fluorescent-tagged versions of receptors, co-receptors, transcription factors and key feedback regulators of the Drosophila BMP and Activin signaling pathways. We demonstrate that the generated alleles are biologically active and can be used for assessing tissue and subcellular distribution of the corresponding proteins. Furthermore, we show that the genomic platforms can be used for in locus structure-function and cis-regulatory analyses. Finally, we present a complementary set of protein binder-based tools, which allow visualization as well as manipulation of the stability and subcellular localization of epitope-tagged proteins, providing new tools for the analysis of BMP signaling and beyond.

Vitamin D receptor and its antiproliferative effect in human pulmonary arterial hypertension

Vitamin D (vitD) deficiency is frequently observed in patients with pulmonary arterial hypertension (PAH) and, in these patients, low levels of vitD correlate with worse prognosis. The aim of this study was to examine the expression and the antiproliferative role of vitD receptor (VDR) and its signalling pathway in the human pulmonary vasculature. VDR presence and expression was analyzed in lungs, pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) from controls and PAH-patients. VDR expression and VDR-target genes were examined in PASMC treated with calcitriol. The antiproliferative effect of 48 h-calcitriol was studied in PASMC by MTT and BrdU assays. VDR is expressed in PASMC. It is downregulated in lungs and in PASMC, but not in PAEC, from PAH-patients compared to non-hypertensive controls. Calcitriol strongly upregulated VDR expression in PASMC and the VDR target genes KCNK3 (encoding TASK1), BIRC5 (encoding survivin) and BMP4. Calcitriol produced an antiproliferative effect which was diminished by silencing or by pharmacological inhibition of survivin or BMPR2, but not of TASK1. In conclusion, the expression of VDR is low in PAH-patients and can be rescued by calcitriol. VDR exerts an antiproliferative effect in PASMC by modulating survivin and the BMP signalling pathway.

Integrin α2β1 deficiency enhances osteogenesis via BMP-2 signaling for accelerated fracture repair

Previous studies have shown that the absence of the collagen-binding integrin α2β1 confers protection against osteoporosis, primarily by enhancing osteoblast-mediated matrix formation, with a particular increase in collagen type I production. This study aimed to elucidate the mechanism underlying this increased matrix production. Our findings demonstrate that osteoblasts lacking integrin α2 secrete a pro-osteogenic factor that activates both TGF-β and BMP signaling pathways. Among these, BMP-2 was identified as the key signaling protein responsible for this effect, as its expression was significantly upregulated during osteoblast differentiation. Moreover, integrin α2 deficiency led to earlier and elevated BMP-2 secretion at the cell surface during osteogenesis, which promoted accelerated osteoblast differentiation. This phenomenon likely contributes to enhanced matrix production in aging animals, providing a protective effect against osteoporosis.To explore the broader implications of this phenotype, we utilized a fracture healing model. In integrin α2-deficient 12 weeks old female mice, elevated serum levels of BMP-2 were detected during the early stages of fracture repair. This upregulation of BMP signaling within the fracture callus accelerated the healing process, resulting in faster formation and mineralization of the cartilaginous callus. Additionally, the elevated BMP-2 levels facilitated earlier differentiation of chondrocytic cells, evidenced by the premature appearance of collagen type II- and type X-positive cells during endochondral ossification. Despite the accelerated healing, the overall biomechanical integrity of the repaired fractures remained uncompromised.Thus, the modulation of integrin α2β1 presents a promising therapeutic target for enhancing fracture repair by regulating BMP-2 signaling in a physiologically relevant manner.

Exploration and identification of diabetes targets in nursing: CDH1 and DVL1.

Diabetes is a chronic disease caused by absolute or relative insufficiency of insulin secretion and impaired insulin utilization. CDH1 and DVL1 role in diabetes and its nursing care is unclear. The diabetes dataset GSE21321 and GSE19790 profiles were downloaded from the gene expression omnibus (GEO) database. Perform differentially expressed genes (DEGs) screening, weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network construction and analysis, functional enrichment analysis, gene set enrichment analysis (GSEA), immune infiltration analysis, and Comparative Toxicogenomics Database (CTD) analysis. Gene expression heat map was drawn. TargetScan was used to screen the miRNA that regulates central DEGs. 1983 DEGs were obtained. According to Gene Ontology (GO) analysis, they were mainly enriched in signal regulation, catenin complexes, and signal receptor binding. In Kyoto Encyclopedia of Gene and Genome (KEGG) analysis, they were mainly concentrated in the Rap1 signaling pathway, cAMP signaling pathway, and Hippo signaling pathway. The DEGs are mainly enriched in cell signaling, Wnt signaling vesicles, growth factor activity, and the interaction between neural active ligands and receptors. In the enrichment project of Metascape, BMP signaling pathways and cell population proliferation can be seen in the GO enrichment project. The soft threshold power in WGCNA is set to 5. A total of 15 modules were generated. Core gene expression heatmap showed that core genes (CTNNB1, CDH1, DVL1) were highly expressed in diabetes samples. CTD analysis showed thatCTNNB1, CDH1, DVL1were associated with weight gain, inflammation, and necrosis. CDH1 and DVL1 are highly expressed in diabetes and may become molecular targets for diabetes and its care.

Changes in gene expression profile of normal human fibroblasts on P(VDF-TrFE) scaffolds highly doped with Fe3O4-CA nanoparticles under alternating magnetic field stimulation

The design of novel hybrid magnetoactive scaffolds based on biocompatible piezopolymers and magnetic nanoparticles is of interest for medicine, mainly for tissue regeneration, because application of an external either static or alternating magnetic field to cells that settled on a magnetoactive scaffold offers an opportunity for remote control of cellular functions. This study describes fabrication of electrospun magnetoactive poly(vinylidene fluoride-co-trifluoroethylene) [P(VDF-TrFE)] scaffolds highly doped with 20 wt% of magnetite nanoparticles modified with citric acid (Fe3O4-CA). The electrospun P(VDF-TrFE)/Fe3O4-CA scaffolds have defect-free morphology with a fiber diameter of approximately 1 μm and contain both an electroactive β-phase (predominantly) and a lesser amount of an γ-phase. A high content of uniformly distributed Fe3O4-CA nanoparticles within P(VDF-TrFE) fibrous scaffolds resulted in a high saturation magnetization of 12.1 emu/g and ferrimagnetic behavior of the composite P(VDF-TrFE)/Fe3O4-CA scaffolds. They were proved to be biocompatible with normal human cells: normal human fibroblasts and human mesenchymal stem cells adhered to the scaffold and retained their viability. According to high-throughput RNA-sequencing data, the adhesion of fibroblasts to the scaffolds upregulated genes related to key stages of tissue regeneration such as coagulation (genes THBD and SERPINB2) and wound healing (IL24, PDGFB, F3, and PLAU) and affected TGFβ, BMP, and Wnt signaling pathways. Alternating-magnetic-field exposure of the magnetoactive P(VDF-TrFE)/Fe3O4-CA scaffolds with fibroblasts settled on the surface activated extracellular and intracellular cell signaling pathways.

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas.

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell, and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell, and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.

Expression profiles of urine exosomal tRNA-derived small RNAs and their potential roles in calcium oxalate stone disease

Background and objective: Exosomes have been confirmed to be implicated in the pathogenesis of calcium oxalate (CaOx) stones. tRNA-derived small RNAs (tsRNAs) are among the oldest small RNAs involved in exosome-mediated intercellular communication, yet their role in kidney stones remains unexplored. This pilot study aimed to identify differentially expressed tsRNAs (DEtsRNAs) in urine exosomes between CaOx stone patients and healthy controls and explore their potential roles in nephrolithiasis. Method: First-morning urine samples were collected from three CaOx stone patients and three healthy controls. Urinary exosomes were isolated and analyzed by high-throughput sequencing to generate the expression profiles of tsRNAs and detect DEtsRNAs. Predicted target genes of DEtsRNAs were subjected to functional enrichment analysis. The authors also combined the public dataset GSE73680 to investigate how DEtsRNAs were related to stone formation. Results: Four DEtsRNAs were significantly upregulated in CaOx stone patients compared to healthy controls. tRF-Lys-TTT-5005c was the most elevated, followed by tRF-Lys-CTT-5006c, tRF-Ala-AGC-5017b, and tRF-Gly-CCC-5004b. Bioinformatics analysis indicated that these four types of DEtsRNAs might serve distinct biological functions. Combined with data mining from the public dataset GSE73680, the authors assumed that exosomes carrying tRF-Lys-TTT-5005c and tRF-Lys-CTT-5006c could inhibit the expression of SMAD6, FBN1, and FZD1, thereby activating the BMP signaling pathway, which might induce an osteogenic-like transformation in target cells, resulting in the formation of Randall’s plaques and CaOx stones. Conclusion: The authors’ findings shed light on the potential roles of tsRNAs in the pathogenesis of CaOx stone disease, highlighting exosomal DEtsRNAs as promising diagnostic biomarkers and therapeutic targets in nephrolithiasis.

MiR4352b a cross-species modulator of SOSTDC1, targets dual pathway to regulate bone health and fracture healing

Mutations in SOST can lead to various monogenic bone diseases. Its paralog, SOSTDC1, shares 55 % protein sequence homology and belongs to the BMP antagonist class. Sostdc1−/− mice exhibit distinct effects on cortical and trabecular bone. Genetic polymorphisms in SOSTDC1 impacting peak bone mass makes SOSTDC1 gene, a candidate for influencing BMD variation in humans. SOSTDC1 is upregulated in bone loss conditions, altering BMP-responsive genes and signaling modulators, suggesting its dual BMP/Wnt antagonist role may enhance both pathways. Overexpression of SOSTDC1 confirmed its role as an osteogenic antagonist. Glycine max (Soy)-derived miR4352b, identified for cross-kingdom applications, precisely targets SOSTDC1, a key regulator of bone. SOSTDC1 competitively binds to BMP2 receptor, BMPR1A. Gma-miR4352b suppresses SOSTDC1 expression, enhancing osteogenesis and countering SOSTDC1's inhibition of osteogenic potential. Modeling estrogen deficiency to mimic elevated SOSTDC1 levels, we observed an inverse correlation with SOSTDC1 expression, while serum BMP2 and PINP levels increased following gma-miR4352b supplementation. In fracture healing, SOSTDC1's crucial role becomes evident in conditions of delayed fracture healing. As healing progresses, SOSTDC1 expression decreases. Gma-miR4352b, compared to scrambled miRNA, remarkably promotes callus formation, achieving 68 % healing by day 10, surpassing the scrambled group at 44 %. By the day 13, the treatment group exhibits advanced healing, challenging to find the callus, while the scrambled group maintains a healing rate similar to day10. The accelerated healing in the treatment group underscores the importance of SOSTDC1 in influencing early fracture healing, potentially through the activation of both BMP2 and Wnt signaling pathways.

Single-cell sequencing of the vermiform appendix during development identifies transcriptional relationships with appendicitis in preschool children

BackgroundThe development of the human vermiform appendix at the cellular level, as well as its function, is not well understood. Appendicitis in preschool children, although uncommon, is associated with a high perforation rate and increased morbidity.MethodsWe performed single-cell RNA sequencing (scRNA-seq) on the human appendix during fetal and pediatric stages as well as preschool-age inflammatory appendices. Transcriptional features of each cell compartment were discussed in the developing appendix. Cellular interactions and differentiation trajectories were also investigated. We compared scRNA-seq profiles from preschool appendicitis to those of matched healthy controls to reveal disease-associated changes. Bulk transcriptomic data, immunohistochemistry, and real-time quantitative PCR were used to validate the findings.ResultsOur analysis identified 76 cell types in total and described the cellular atlas of the developing appendix. We discovered the potential role of the BMP signaling pathway in appendiceal epithelium development and identified HOXC8 and PITX2 as the specific regulons of appendix goblet cells. Higher pericyte coverage, endothelial angiogenesis, and goblet mucus scores together with lower epithelial and endothelial tight junction scores were found in the preschool appendix, which possibly contribute to the clinical features of preschool appendicitis. Preschool appendicitis scRNA-seq profiles revealed that the interleukin-17 signaling pathway may participate in the inflammation process.ConclusionsOur study provides new insights into the development of the appendix and deepens the understanding of appendicitis in preschool children.Graphical

Inhibition of KDM2/7 Promotes Notochordal Differentiation of hiPSCs.

Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal diseases. Therefore, adult somatic cells reprogrammed into human induced pluripotent stem cells (hiPSCs) represent an attractive cell source for the derivation of notochordal-like cells (NCs) as a first step towards the development of a regenerative therapy for IDD. Utilizing a differentiation method involving treatment with a four-factor cocktail targeting the BMP, FGF, retinoic acid, and Wnt signaling pathways, we differentiate CRISPR/Cas9-generated mCherry-reporter knock-in hiPSCs into notochordal-like cells. Comprehensive analysis of transcriptomic changes throughout the differentiation process identified regulation of histone methylation as a pivotal driver facilitating the differentiation of hiPSCs into notochordal-like cells. We further provide evidence that specific inhibition of histone demethylases KDM2A and KDM7A/B enhanced the lineage commitment of hiPSCs towards notochordal-like cells. Our results suggest that inhibition of KDMs could be leveraged to alter the epigenetic landscape of hiPSCs to control notochord-specific gene expression. Thus, our study highlights the importance of epigenetic regulators in stem cell-based regenerative approaches for the treatment of disc degeneration.