Global Wnt Inhibition with the Porcupine Inhibitor, LGK974, Decreases Trabecular Bone in a Murine Model with Fibrotic Bone
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1027000 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26357347.fastq.gz | Fastqsanger.gz | |||
| SRR26357348.fastq.gz | Fastqsanger.gz | |||
| SRR26357349.fastq.gz | Fastqsanger.gz | |||
| SRR26357350.fastq.gz | Fastqsanger.gz | |||
| SRR26357351.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 16 |
Similar Datasets
Project description:G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by an activating mutation in GNAS. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD, for which there are no effective medical treatments.The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remains largely unknown. Single cell RNA sequencing on long-bone stromal cells of 9-week-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or down-regulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.
2023-10-16 | GSE245140 | GEO
Project description:RNA sequencing with differential gene expression analysis was performed on AsPC-1 pancreatic ductal adenocarcinoma (PDAC) cells at multiple time points with a Porcupine inhibitor (LGK974) to identify mechanisms underpinning transcriptional effects.
2022-04-19 | GSE180615 | GEO
Project description:G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by activating mutations in GNAS. There are no effective therapies for FD. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages using an engineered receptor strategy, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD. The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remain largely unknown. Single-cell RNA sequencing on long-bone stromal cells of 9-wk-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or downregulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.
| S-EPMC10994528 | biostudies-literature
Project description:The LAD of C57BL6 mice were temporally occluded to induce ischemia-reperfusion injury of the heart. Mice received a daily dose of the porcupine inhibitor LGK974 starting directly after the surgery to prevent Wnt protein secretion. Control animals received a DMSO vehicle control. Hearts were extracted 48h after induction of ischemia-reperfusion injury. The infarcted area was identified and processed for RNAseq analysis.
2022-11-02 | GSE185444 | GEO
Project description:scRNA for 8wks trabecular bone
| PRJNA684133 | ENA
Project description:This SuperSeries is composed of the following subset Series:; GSE12264: Gene Expression Profile of Osteogenic Cells Derived from Human Bone Marrow and Trabecular Bone I; GSE12265: Gene Expression Profile of Osteogenic Cells Derived from Human Bone Marrow and Trabecular Bone II; GSE12266: Gene Expression Profile of Osteogenic Cells Derived from Human Bone Marrow and Trabecular Bone III Experiment Overall Design: Refer to individual Series
2008-10-21 | E-GEOD-12267 | biostudies-arrayexpress
Project description:Here we provide proteomic datasets of pairs of cortical and trabecular bone from six Early Holocene Caprinae rib fragments from the site of La Draga, Spain, using shotgun proteomics. Our observations on proteome size and protein, peptide, and amino acid degradation have implications for the sampling of archaeological skeletal remains in highly degraded proteomic contexts, where preference should be given to the sampling of cortical bone in order to maximise the retrieval of larger and better-preserved skeletal proteomes.
2024-07-12 | PXD047126 | Pride
Project description:High-throughput microRNA sequencing was used to identify microRNAs (miRs) that regulate osteoblast differentiation. We establish that miR-101a, which targets the epigenetic enzyme Ezh2, is up-regulated in differentiated MC3T3 cells and robustly expressed in mouse calvaria. Our previous studies showed that loss of Ezh2 function enhances osteogenesis and bone formation. Thus, we tested the attractive mechanistic model that increased miR-101s expression may suppress Ezh2 to stimulate the osteogenic process. Transient miR-101a over-expression suppresses Ezh2 levels and reduces tri-methylation on lysine 27 of histone 3 (H3K27me3), a heterochromatic mark catalyzed by Ezh2. Importantly, over-expression of miR-101a stimulates osteogenic differentiation of MC3T3 cells as quantified by alizarin red staining. Therefore, we examined skeletal phenotypes of mice transgenic for miR-101a under the control of Col1a1promoer and doxycycline administration. Experimental controls and mir-101 over-expressing mice were exposed to doxycycline during pregnancy and postnatal stages (phenotyping at 8 weeks) to maximize penetrance of skeletal phenotypes. Our analyses revealed that miR-101a over-expressing male mice are bigger as measured by total body weight and exhibit an increase in long bone length. These mice exhibit significant increases in trabecular bone volume fraction, trabecular number, trabecular thickness, as well as a reduction in trabecular spacing based on microCT analysis. Histomorphometric examination established a significant reduction in osteoid volume to bone volume and osteoid surface to bone surface. These findings suggest that the enhancement in trabecular bone may be due to accelerated bone mineralization in miR-101a over-expressing male mice. Remarkably, while female mice exhibit a significant increase in bone length, no significant changes were noted by microCT (trabecular bone parameters) and histomorphometry (osteoid parameters). We conclude that miR-101a upregulation during osteoblast maturation enhances trabecular bone parameters in male mice. Thus, miR-101 and Ezh2 may form part of an intricate epigenetic feed-forward mechanisms to regulate bone formation.
2021-01-01 | GSE155390 | GEO
Project description:microRNA-101a enhances trabecular bone accrual in male mice
| PRJNA649561 | ENA
Project description:Human papilloma virus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT-signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT-ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/b-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT-secretion may thus represent a promising approach for therapeutic intervention.
2018-12-13 | GSE108454 | GEO