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ZBTB20 triggerring PI3K/AKT-NF-kappaB signaling requires the suppression of Pten

ABSTRACT: Better understanding of the early molecular events and underlying mechanism will benefit the early-stage diagnose and clinical therapy of OA. In this study, we demonstrated the functions of ZBTB20 in OA pathogenesis via regulating ECM homeostasis. Chondrocytes-specific depletion of Zbtb20 in adult mice attenuated DMM-induced OA progress, restored the balance of ECM anabolism and catabolism. To investigate the underlying mechanism of ZBTB20 in OA progress, RNA-seq was carried out using cultured primary chondrocytes from control and Zbtb20-cKO mice, treated by IL-1β.

ORGANISM(S): Mus musculus

PROVIDER: GSE269579 | GEO | 2025/03/19

REPOSITORIES: GEO

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Both TRULI and DAPA may serve as anti-OA drugs by modulating ZBTB20 to restore ECM homeostasis

Project description:Due to the existing challenges in modulating the activity of transcription factors directly, comprehending the upstream regulatory mechanism can offer perspectives for tackling these obstacles. Our observations that in early-stage OA chondrocytes ZBTB20 translocates into nucleus in a LATS1-dependent manner, triggers NF-κB signaling and enhances ECM degradation, leads us to consider different approaches to restore ECM balance: either by inhibiting LATS1 to impede ZBTB20 activity or by directly reducing ZBTB20 expression. The small molecular compound TRULI can block the nucleus accumulation of ZBTB20 via inhibiting LATS1 phosphorylation, and DAPA was identified as a proposing drug targeting Zbtb20.Our results demonstrated that pharmacologic blockade of LATS1 by TRULI, as well as inhibition of Zbtb20 expression by DAPA, restored the ECM homeostasis in chondrocytes and minimized matrix degradation in human articular cartilage explants.

2025-03-19 | GSE269735 | GEO

Skatole attenuates osteoarthritis by protecting chondrocytes and mediating macrophage repolarization through regulating the NFκB/MAPK signaling pathway and metabolic reprogramming II

Project description:Osteoarthritis (OA) is the most common joint disease, but there are currently no disease-modifying OA drugs (DMOADs) yet approved by the regulatory agencies. Regulating macrophage polarization can alleviate synovial inflammation and then repair articular cartilage damage, providing a new target for OA treatment. Here, we found that Skatole can modulate macrophage polarization and attenuate OA. Skatole hindered M1 macrophage polarization while promoting M2 macrophage polarization. Mechanistically, Skatole activated Stat6, suppressed the phosphorylation of IKK, IκBα, and p65 in NFκB signaling pathway, and inhibited MAPK signaling activation. RNA-seq analysis revealed that Skatole downregulated the expression of inflammation-related genes, while upregulating genes involved in glutathione metabolism and oxidative phosphorylation, thereby reducing ROS levels and inhibiting M1 macrophage polarization. Moreover, conditional medium (CM) from M1 macrophages treated with Skatole balanced anabolism and catabolism in mouse chondrocytes while inhibiting cell apoptosis. Intriguingly, in IL1β-treated chondrocytes, Skatole directly suppressed inflammation and catabolism, without significantly affecting cell apoptosis or anabolism; In vivo experiments showed that Skatole increased M2 polarization and decreased M1 polarization of synovial macrophages, alleviated synovitis, and lessend articular cartilage damage in destabilization of medial meniscus (DMM)-induced OA mice. Our finding suggest that Skatole has the potential to function as a DMOAD.

2025-02-12 | GSE283748 | GEO

Skatole attenuates osteoarthritis by protecting chondrocytes and mediating macrophage repolarization through regulating the NFκB/MAPK signaling pathway and metabolic reprogramming

2025-02-12 | GSE261400 | GEO

Transcript profile comparison of Zbtb20-sufficient and Zbtb20-deficient polyclonal bone marrow plasma cells

Project description:ZBTB20 is an adjuvant-specific factor for long-term antibody responses. This factor is critical for maintaining long-lived plasma cells in alum-adjuvanted antibody responses but is dispensable for TLR ligand-adjuvanted responses. To identify the functions of ZBTB20 in long-lived plasma cells, we performed microarray analysis on Zbtb20-sufficient and Zbtb20-deficient polyclonal bone marrow plasma cells under the assumption that ZBTB20 regulates relevant targets in all long-lived plasma cells, irrespective of their mode of formation. Chimeras were generated using Zbtb20-sufficient (WT) or Zbtb20-deficient (TRAP) E14.5 fetal livers. 3-4 months after reconstitution, donor bone marrow B220low/-CD138+ cells (4 replicates per genotype) were purified via FACS for microarray. In total, 8 samples, 4 for each genotype, were included in this study.

2014-06-19 | E-GEOD-58659 | biostudies-arrayexpress

Role of TET1 Mediatd 5hmC in Osteoarthritis [RRHP]

Project description:No disease-modifying drugs exist to treat osteoarthritis (OA), a degenerative disease of the joint. The complexity of OA necessitates a combinational and broad therapeutic approach. Epigenetic regulators are able to control large programs of genes, and recent work from our group and others have showcased systemic epigenetic dysregulation in OA. Previously, we demonstrated that OA chondrocytes accumulate 5-fold more 5-hydroxymethylcytosine (5hmC), an oxidized derivative of methylcytosine (5mC) associated with gene activation, at disease relevant sites. To test if 5hmC has a role in the early onset of OA, we utilized a mouse model of surgically induced OA, destabilization of the medial meniscus (DMM), and found that DMM mice gained ~40,000 differentially hydroxymethylated sites. Genetic loss of TET1, the enzyme responsible for 5hmC deposition, prevented pathologic gain of 5hmC, activation of many OA pathways, and protected mice from OA development. To test the clinical potential of a TET1 based OA therapy, we injected 2-hydroxyglutarate (2-HG), a TET inhibitor, into the joint after DMM induction and observed stalled disease progression. Collectively, these data show that TET1 mediated 5hmC deposition regulates multiple OA pathways and that its modulation can be a powerful clinical tool for OA.

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Role of TET1 Mediated 5hmC in Osteoarthritis [RNA-seq]

2020-07-13 | GSE143447 | GEO

Integration of transcriptomic and epigenomic analyses uncovered Lrrc15 as a potential contributing factor to cartilage damage in osteoarthritis

Project description:Objective: We used the destabilization of the medial meniscus (DMM) model to identify temporal changes in DNA methylation patterns associated with structural and transcriptomic changes in cartilage during osteoarthritis (OA) progression. Methods: RNA sequencing (RNAseq) and Reduced Representation Oxidative Bisulfite Sequencing (RRoxBS) analyses were done in total RNA and DNA obtained from micro-dissected cartilage at 4 and 12 weeks after DMM surgery. Murine and human primary chondrocytes were used to evaluate the cytokine- and methylation-dependent changes in the expression of Lrrc15, and its contribution to IL-1beta-induced changes in chondrocytes. Results: We identified time-dependent alterations in epigenomic patterns in cartilage after DMM, with significant changes in 5mC and 5hmC methylation comparing samples retrieved at 4 and 12 weeks after surgery. Integration of RNAseq and RRoxBS datasets identified Lrrc15 as a hypomethylated gene with increased expression at 4 weeks after surgery. We confirmed LRRC15 immunostaining in OA cartilage, and experiments in human and murine primary chondrocytes showed that the expression of Lrrc15 is DNA methylation-dependent and induced by IL1beta and TNFalfa in vitro. Knockdown experiments showed that Lrrc15 contributes to the IL1beta-driven expression of catabolic genes relevant to OA, including Mmp13. Significance: Our integrative analyses showed that the structural progression of OA is accompanied by transcriptomic and dynamic epigenomic changes in articular cartilage. We found that Lrrc15 is differentially methylated and expressed in OA cartilage, and that it may contribute to the cytokine-driven responses of OA chondrocytes. A better understanding of the role of Lrrc15 in cartilage homeostasis and osteoarthritis may help us uncover targets with therapeutic potential.

2021-09-01 | GSE175486 | GEO

Transcript profile comparison of Zbtb20-sufficient and Zbtb20-deficient polyclonal bone marrow plasma cells

2014-06-19 | GSE58659 | GEO

Both TRULI and DAPA may serve as anti-OA drugs by modulating ZBTB20 to restore ECM homeostasis

Project description:Both TRULI and DAPA may serve as anti-OA drugs by modulating ZBTB20 to restore ECM homeostasis

| PRJNA1123580 | ENA

Transcriptome analysis after GPX4 knockdown in primary mouse chondrocyte（mcc）

Project description:Osteoarthritis (OA) is the most common joint disease and is the leading cause of chronic disability among older people. Chondrocyte death was involved in OA pathogenesis. Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. Expression of GPX4 in the OA cartilage from OA patients were significantly lower than normal cartilage.In order to analyze the mechanism of GPX4, we conducted RNA-sequencing in mouse chondrocytes with or without GPX4 knockdown.Our results showed that Gpx4 downregulation could increase the sensitivity of chondrocytes to oxidative stress and aggravate ECM degradation in chondrocytes.

2022-02-18 | GSE190184 | GEO

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