β-Ecdysterone Enhanced Bone Regeneration Through The BMP-2/SMADs/RUNX2/Osterix Signaling Pathway
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ABSTRACT:
PROVIDER: PRJNA813351 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18249764_1.fastq.gz | Fastqsanger.gz | |||
| SRR18249764_2.fastq.gz | Fastqsanger.gz | |||
| SRR18249765_1.fastq.gz | Fastqsanger.gz | |||
| SRR18249765_2.fastq.gz | Fastqsanger.gz | |||
| SRR18249766_1.fastq.gz | Fastqsanger.gz |
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Project description:Bone defects are a global public health problem. However, the available methods for bone regeneration are limited. In recent years, the application of traditional Chinese herbs for bone regeneration has attracted increasing attention. β-ecdysterone is a herbal extract similar to estrogen that promotes the metabolism of cell protein synthesis; however, its function on bone regeneration is not yet clear. In this study, we investigated the function of β-ecdysterone on osteoblast differentiation and bone regeneration in vitro and in vivo. MC3T3-E1 cells were used to test the function of β-ecdysterone on osteoblast differentiation and bone regeneration in vitro. The results of the CCK-8 assay suggested that the proliferation of MC3T3-E1 cells was promoted by β-ecdysterone. Furthermore, β-ecdysterone influenced the expression of osteogenesis-related genes, and the bone regeneration capacity of MC3T3-E1 cells was detected by PCR, the alkaline phosphatase (ALP) test, and the Alizarin Red test. β-ecdysterone could up-regulate the expression of osteoblastic-related genes, and promoted ALP activity and the formation of calcium nodules. Moreover, we also determined that β-ecdysterone increased the mRNA and protein levels of components of the BMP-2/Smad/Runx2/Osterix pathway. DNA sequencing further confirmed these target effects. β-ecdysterone promoted bone formation by enhancing gene expression of the BMP-2/Smad/Runx2/Osterix signaling pathway and by the enrichment biological processes. For in vivo experiments, the femur condyle defection model was constructed by drilling a critical-sized (3×3 mm) defect in 12-week-old SD male rats to further assess the bone regeneration functions of β-ecdysterone. The results of micro-CT showed that β-ecdysterone could accelerate bone regeneration and exhibited higher bone volume, bone surface, bone mineral density at each observation time point. Immunohistochemistry confirmed that the β-ecdysterone also increased the expression of collagen, osteocalcin, and BMP2 in the experiment group at 8 weeks. In conclusion, discovered β-ecdysterone is a new bone regeneration regulator that can stimulate MC3T3-E1 cell proliferation and induce bone regeneration through the BMP-2/Smad/Runx2/Osterix pathway. This new function of β-ecdysterone has revealed a new direction of osteogenic differentiation and has provided novel therapeutic strategies for treating bone defection.
2022-03-09 | GSE198010 | GEO
Project description:Gene-specific transcription factors (GSTFs) control of gene transcription by DNA binding and specific protein complex recruitment, which regulates promoter accessibility for transcription initiation by RNA polymerase II. GSTFs that are frequently mutated in colon and rectal carcinomas are Suppressor of Mothers Against Decapentaplegic 2 (SMAD2) and SMAD4, which play an important role in the TGF-β signaling pathways controlling cell fate and proliferation (ref.). The SMAD protein family is a diverse and it can be divided into three subclasses: receptor activated SMADs, inhibitory SMADs and the common SMAD4 co-activator. To study protein interactors of the SMAD protein family we generated a quantitative proteomics pipeline that allows for inducible expression of GFP-tagged SMAD proteins followed by affinity purification and MS analysis. The nuclear importin IPO5 was identified as a novel interacting protein of SMAD1. Overexpression of IPO5 shows forced BMP R-SMAD nuclear localization confirming a functional relationship between BMP but not TGF-β R-SMADs and IPO5. Finally we provide evidence that the length of the lysine stretch in the NLS is involved in importin selection.
2016-10-10 | PXD004529 | Pride
Project description:Bone morphogenetic proteins induce neuronal and astrocytic differentiation in mid-gestational (e.g. E11+2DIV), and late-gestational (e.g. E14+5DIV) neural stem cells (NSCs), respectively. We found that Smads, downstream transcription factors of BMP signaling, target dramatically different genomic regions in the neurogenic and gliogenic NSCs. The purpose of this study is to understand histone H3K27 tri-methylation profiles around Smads-binding sites in neurogenic and gliogenic NSCs, and uncover the mechanisms underlying distinct effects of BMPs on developmentally different NSCs. We found that histone H3K27 tri-methylation around Smads binding sites quickly change as gestation proceeds, strongly associated with the alteration of accessibility of Smads to the regions.
2021-11-16 | GSE174306 | GEO
Project description:The goal of this scRNA-seq study was to characterize the pseudo-spatial distribution of Nodal and BMP effectors (SMADs) expression prior to the onset of gastrulation
2021-04-11 | GSE164574 | GEO
Project description:Dental pulp was extracted from mandibular first molars of Osterix-Cre:Tgfbr2wt/wt and Osterix-Cre:Tgfbr2f/f pups on postnatal day 7. 1ng-limiting cell RNA Sequence analysis was performed on 4 samples from each genotype.
2022-02-02 | GSE190582 | GEO
Project description:In Drosophila, efferent neurons gain access to a target-derived BMP signal in the periphery that is required for differentiation and/or synaptic growth and neurotransmission. This requires transcriptional activity of the BMP-activated Smad transcription factors, but the Smad-bound enhancers and BMP-regulated effector genes they control remain unidentified. In the absence of insight into how BMP signaling controls these fundamental aspects of neuronal development and function, here we test whether Smads act directly at widely-deployed archetypal Smad-binding motifs to directly co-regulate batteries of BMP-responsive genes. To target these motifs for analysis, we employed a bioinformatics approach to identify candidate motifs conforming to the consensus 15bp BMP-Activation Element (BMP-AE). After filtering for high conservation and proximity to neuronally-expressed genes, we prioritized 62 BMP-AEs for analysis. Testing the in vivo enhancer activity of 58 genomic fragments containing these BMP-AEs in transgenic reporters, we show that 61% are functional BMP enhancers in diverse motoneuron and neuropeptidergic neuronal populations, and that the BMP-AE motif itself is required for activity. Moreover, 60% of these functional BMP-AEs were located within 20kb of at least one BMP activated gene, as identified by RNAseq analysis. Finally, we show that the BMP-AE motif plays a conserved activator function in the vertebrate nervous system, by electroporation in the developing chick neural tube. Our results provide evidence that BMP signaling controls neuronal development and function by directly coordinating networks of genes through widespread deployment of conserved, consensus Smad-binding motifs.
2018-10-25 | GSE106650 | GEO
Project description:Runx2 and Axin2 regulate skeletal development. We recently determined that Axin2 and Runx2 molecularly interact in differentiating osteoblasts to regulate intramembranous bone formation, but the relationship between these factors in endochondral bone formation was unresolved. To address this, we examined the effects of Axin2 deficiency on the cleidocranial dysplasia (CCD) phenotype of Runx2+/- mice, focusing on skeletal defects attributed to improper endochondral bone formation. Axin2 deficiency unexpectedly exacerbated calvarial components of the CCD phenotype in the Runx2+/- mice; the endocranial layer of the frontal suture, which develops by endochondral bone formation, failed to mineralize in the Axin2-/-:Runx2+/-mice, resulting in a cartilaginous, fibrotic and larger fontanel than observed in Runx2+/- mice. Transcripts associated with cartilage development (e.g., Acan, miR140) were expressed at higher levels, whereas blood vessel morphogenesis transcripts (e.g., Slit2) were suppressed in Axin2-/-:Runx2+/-calvaria. Cartilage maturation was impaired, as primary chondrocytes from double mutant mice demonstrated delayed differentiation and produced less calcified matrix in vitro. The genetic dominance of Runx2 was also reflected during endochondral fracture repair, as both Runx2+/- and double mutant Axin2-/-:Runx2+/- mice had enlarged fracture calluses at early stages of healing. However, by the end stages of fracture healing, double mutant animals diverged from the Runx2+/- mice, showing smaller calluses and increased torsional strength indicative of more rapid end stage bone formation as seen in the Axin2-/- mice. Taken together, our data demonstrate a dominant role for Runx2 in chondrocyte maturation, but implicate Axin2 as an important modulator of the terminal stages of endochondral bone formation. 4 mice per genotype X 4 genotypes: wildtype (WT), Runx2+/- (R-Het), Axin2-/- (A-KO), Axin2-/-:Runx2+/- (A-KO:R-Het). Total = 16 samples
2014-07-04 | E-GEOD-59079 | biostudies-arrayexpress
Project description:Runx2 and Axin2 regulate skeletal development. We recently determined that Axin2 and Runx2 molecularly interact in differentiating osteoblasts to regulate intramembranous bone formation, but the relationship between these factors in endochondral bone formation was unresolved. To address this, we examined the effects of Axin2 deficiency on the cleidocranial dysplasia (CCD) phenotype of Runx2+/-M-BM- mice, focusing on skeletal defects attributed to improper endochondral bone formation. Axin2 deficiency unexpectedly exacerbated calvarial components of the CCD phenotype in the Runx2+/-M-BM- mice; the endocranial layer of the frontal suture, which develops by endochondral bone formation, failed to mineralize in the Axin2-/-:Runx2+/-mice, resulting in a cartilaginous, fibrotic and larger fontanel than observed in Runx2+/-M-BM- mice. Transcripts associated with cartilage development (e.g., Acan, miR140) were expressed at higher levels, whereas blood vessel morphogenesis transcripts (e.g., Slit2) were suppressed in Axin2-/-:Runx2+/-calvaria. Cartilage maturation was impaired, as primary chondrocytes from double mutant mice demonstrated delayed differentiation and produced less calcified matrix in vitro. The genetic dominance of Runx2 was also reflected during endochondral fracture repair, as both Runx2+/-M-BM- and double mutant Axin2-/-:Runx2+/-M-BM- mice had enlarged fracture calluses at early stages of healing. However, by the end stages of fracture healing, double mutant animals diverged from the Runx2+/-M-BM- mice, showing smaller calluses and increased torsional strength indicative of more rapid end stage bone formation as seen in the Axin2-/-M-BM- mice. Taken together, our data demonstrate a dominant role for Runx2 in chondrocyte maturation, but implicate Axin2 as an important modulator of the terminal stages of endochondral bone formation. 4 mice per genotype X 4 genotypes: wildtype (WT), Runx2+/- (R-Het), Axin2-/- (A-KO), Axin2-/-:Runx2+/- (A-KO:R-Het). Total = 16 samples
2014-07-04 | E-GEOD-59081 | biostudies-arrayexpress
Project description:Background: Prostate cancer (PCa) cells preferentially metastasize to bone at least in part by acquiring osteomimetic properties. Runx2, an osteoblast master transcription factor, is aberrantly expressed in PCa cells, and promotes their metastatic phenotype. The transcriptional programs regulated by Runx2 have been extensively studied during osteoblastogenesis, where it activates or represses target genes in a context-dependent manner. However, little is known about the gene regulatory networks influenced by Runx2 in PCa cells. We therefore investigated genome-wide mRNA expression changes in PCa cells in response to Runx2. Results: We engineered a C4-2B PCa sub-line called C4-2B/Rx2dox, in which doxycycline (Dox) treatment stimulates Runx2 expression from very low levels to levels observed in other PCa cells. Transcriptome profiling using whole genome expression array followed by in silico analysis indicated that Runx2 upregulated a multitude of genes with prominent cancer-associated functions. They included secreted factors (CSF2, SDF-1), proteolytic enzymes (MMP9, CST7), cytoskeleton modulators (SDC2, Twinfilin, SH3PXD2A), intracellular signaling molecules (DUSP1, SPHK1, RASD1) and transcription factors (Sox9, SNAI2, SMAD3) functioning in epithelium to mesenchyme transition (EMT), tissue invasion, as well as homing and attachment to bone. Consistent with the gene expression data, induction of Runx2 in C4-2B cells enhanced their invasiveness. It also promoted cellular quiescence by blocking the G1/S phase transition during cell cycle progression. Furthermore, the cell cycle block was reversed as Runx2 levels declined after Dox withdrawal. Conclusions: The effects of Runx2 in C4-2B/Rx2dox cells, as well as similar observations made by employing LNCaP, 22RV1 and PC3 cells, highlight multiple mechanisms by which Runx2 promotes the metastatic phenotype of PCa cells, including tissue invasion, homing to bone and induction of high bone turnover. Runx2 is therefore an attractive target for the development of novel diagnostic, prognostic and therapeutic approaches to PCa management. Targeting Runx2 may prove more effective than focusing on its individual downstream genes and pathways. C4-2B/Rx2dox cells were subjected to microarray gene expression analysis after one and two days of treatment with either Dox or vehicle in biological quadruplicates (a total of 16 samples).
2010-12-26 | E-GEOD-24261 | biostudies-arrayexpress
Project description:Runx2 and Axin2 regulate skeletal development. We recently determined that Axin2 and Runx2 molecularly interact in differentiating osteoblasts to regulate intramembranous bone formation, but the relationship between these factors in endochondral bone formation was unresolved. To address this, we examined the effects of Axin2 deficiency on the cleidocranial dysplasia (CCD) phenotype of Runx2+/- mice, focusing on skeletal defects attributed to improper endochondral bone formation. Axin2 deficiency unexpectedly exacerbated calvarial components of the CCD phenotype in the Runx2+/- mice; the endocranial layer of the frontal suture, which develops by endochondral bone formation, failed to mineralize in the Axin2-/-:Runx2+/-mice, resulting in a cartilaginous, fibrotic and larger fontanel than observed in Runx2+/- mice. Transcripts associated with cartilage development (e.g., Acan, miR140) were expressed at higher levels, whereas blood vessel morphogenesis transcripts (e.g., Slit2) were suppressed in Axin2-/-:Runx2+/-calvaria. Cartilage maturation was impaired, as primary chondrocytes from double mutant mice demonstrated delayed differentiation and produced less calcified matrix in vitro. The genetic dominance of Runx2 was also reflected during endochondral fracture repair, as both Runx2+/- and double mutant Axin2-/-:Runx2+/- mice had enlarged fracture calluses at early stages of healing. However, by the end stages of fracture healing, double mutant animals diverged from the Runx2+/- mice, showing smaller calluses and increased torsional strength indicative of more rapid end stage bone formation as seen in the Axin2-/- mice. Taken together, our data demonstrate a dominant role for Runx2 in chondrocyte maturation, but implicate Axin2 as an important modulator of the terminal stages of endochondral bone formation.
2014-07-04 | GSE59081 | GEO