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Glutamine inhibited hyperglycolysis to curb lactylation of AMPKα to accelerate extracellular matrix synthesis and autophagy and restrain senescence in nucleus pulposus cell

ABSTRACT: IDD (Intervertebral disc degeneration) is an important cause of low back pain which has become a global public health problem. We aimed to determine the role of glutamine in the development of IDD and evaluate its mechanism to prevent IDD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226186 | GEO | 2024/03/20

REPOSITORIES: GEO

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Glutamine inhibited hyperglycolysis to curb lactylation of AMPKα to accelerate extracellular matrix synthesis and autophagy and restrain senescence in nucleus pulposus cell

Project description:Glutamine inhibited hyperglycolysis to curb lactylation of AMPKα to accelerate extracellular matrix synthesis and autophagy and restrain senescence in nucleus pulposus cell

| PRJNA939141 | ENA

miR-seq analysis of nucleus pulposus tissues from compression-induced intervertebral disc degeneration rats

Project description:Intervertebral disc degeneration (IDD) is an important cause of low back pain. And abnormal mechanical factors are an important contributor to IDD. To identify mechanical responsive miRNAs in IDD, we used a custom-made compression device to establish IDD in rats and considered as IDD group, and the Sham group was inserted with K-wires into coccyxes only. After four weeks, rat nucleus pulposus tissues were obtained for miR-seq analysis.

2024-06-20 | GSE230509 | GEO

Nucleus pulposus related lncRNA and mRNA expression profiles in intervertebral disc degeneration

Project description:Intervertebral disc degeneration (IDD) leads to low back pain and disability globally. The pathophysiology of IDD is not entirely understood. There is increasing evidence that long noncoding RNAs (lncRNAs) play a key regulatory role in a wide range of biological processes. The purpose of this study was to comprehensively lncRNA and mRNA expression profiles of human intervertebral disc (IVD) tissues, specifically nucleus pulpous (NP) tissues, with early and advanced stages of disc degeneration. The overview of lncRNA and mRNA expression profiles in the current study revealed that differentially expressed lncRNAs and mRNAs were identified that have been reported to be relevant to IDD. Importantly, differentially expressed lncRNAs and mRNAs that regulate the major signaling pathways, such as NF-κB, MAPK, and Wnt signaling, that are well known to be responsible for the pathogenesis of IDD.

2023-02-09 | GSE186542 | GEO

Discovery and application of postnatal nucleus pulposus progenitors essential for intervertebral disc homeostasis and degeneration.

Project description:Intervertebral disc degeneration (IDD) results from dysfunction of nucleus pulposus cells (NPs) and exhaustion of NP progenitors (ProNPs). Cellular applications of NPs during IDD are currently limited by lack of in vivo studies showing whether NPs are heterogenous and contain ProNPs throughout postnatal stages. Here, using single-cell RNA sequencing of purified NPs, we mapped four molecularly defined populations and identified Urotensin II receptor (UTS2R)-expressing postnatal ProNPs, which markedly exhausted during IDD, in mouse and human specimens. Lineage tracing showed that UTS2R+ ProNPs preferentially reside in the NP periphery with its niche factor-Tenascin-C and give rise to functional NPs. We also demonstrate that transplanting UTS2R+ ProNPs with Tenascin-C to injured intervertebral discs attenuates the progression of IDD. Our findings provide a novel NP cell atlas, identify resident ProNPs with regenerative potential and reveal promising diagnostic and therapeutic targets for IDD.

2024-12-30 | GSE192789 | GEO

Transcriptomics study reveals the underlying molecular mechanisms of circadian gene Bmal1 in rat nucleus pulposus cells

Project description:Intervertebral disc degeneration (IDD) is a major cause of low back pain (LBP), and the pathogenesis remains unknown. Recently, an autoregulating circadian rhythm was identiﬁed in intervertebral discs (IVDs), the abolition of which led to IDD. The genetic disruption of the mouse IVD molecular clock, speciﬁcally through the disruption of Bmal1, predisposes mice to IDD. However, the precise role of circadian gene Bmal1 in IDD remain elusive. In this study, RNA-seq was used to determine differentially expressed genes (DEGs) in rat nucleus pulposus cells (NPCs) treated with Bmal1 shRNA or its negative control lentivirus. GO and KEGG pathway analysis were also performed. In general, 6900 DEGs was identified. The anabolic genes, such as col2a1 and acan, showed significantly decreased expression, whereas catabolic genes, such as MMP-3 and MMP-13, showed significantly upregulated expression. GO analysis was performed to annotate the functions of the DEGs. The DEGs were primarily associated with the processes of cell transcription, behaviour, signal transduction, biological regulation, and protein binding. KEGG pathway analysis revealed that Bmal1 was related to multiple signalling pathways, such as p53, Hedgehog, Wnt, PI3K-Akt, mTOR, Hippo and MAPK. This study, for the first time, analyzes the transcriptome of NPCs in response to Bmal1 diminished, indicating that circadian gene Bmal1 is involved in the establishment and progression of IDD through its wide effects on the viability and function of NPCs.

2024-10-15 | GSE186048 | GEO

Proteomic and phosphoproteomic landscape reveals the functional contributions of circadian gene Bmal1 in rat nucleus pulposus cells

2021-10-21 | PXD029273 |

Self-amplifying Loop of NF-κB and Periostin Initiated by PIEZO1 Accelerates Mechano-induced Senescence of Nucleus Pulposus Cells and Intervertebral Disc Degeneration

Project description:Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. Additionally, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced cellular senescence and IDD progression is not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs senescence via NF-κB signaling. Subsequently, we identified periostin as the main mechano-responsive molecule in hNPCs through unbiased sequencing, which was transcriptionally upregulated by NF-κB p65; moreover, secreted periostin by senescent hNPCs further promoted senescence and upregulated the catabolic process in hNPCs through activating NF-κB, forming a positive loop. Both Postn (encoding periostin) knockdown via siRNA and periostin inactivation via neutralizing antibodies alleviated IDD and NPCs senescence. Furthermore, we found that mechano-stress initiated the positive feedback of NF-κB and periostin via PIEZO1. PIEZO1 activation by Yoda1 induced severe IDD in rat tails without compression, and Postn knockdown alleviated the Yoda1-induced IDD in vivo. Here, we reported for the first time that self-amplifying loop of NF-κB and periostin initiated via PIEZO1 under mechano-stress accelerated NPCs senescence, leading to IDD. Furthermore, periostin neutralizing antibodies, which may serve as potential therapeutic agents for IDD, interrupted this loop.

2022-06-06 | GSE185728 | GEO

Shared and compartment-specific processes in nucleus pulposus and annulus fibrosus during intervertebral disc degeneration

Project description:Elucidating how cell populations promote onset and progression of intervertebral disc degeneration (IDD) has the potential to enable more precise therapeutic targeting of cells and mechanisms. Single cell RNA-sequencing (scRNA-seq) was performed on surgically separated annulus fibrosus (AF) (19,978; 26,983 cells) and nucleus pulposus (NP) (20,884; 24,489 cells) from healthy and diseased human intervertebral discs (IVD). In both tissue types, we observed depletion of cell subsets involved in maintenance of healthy IVD, specifically the immature cell subsets – fibroblast progenitors and stem cells – indicative of an impairment of normal tissue self-renewal. We also identified tissue-specific changes. In NP, several fibrotic populations were increased in degenerated IVD, indicating tissue-remodeling. In degenerated AF, we identified a novel disease-associated subset, which is a stem cell-derived abnormally differentiated chondrocytic population and expresses disease-promoting genes. It was associated with pathogenic biological processes and the main gene regulatory networks includedthrombospondinsignaling and FOXO1 transcription factor. Our data reveal new insights of both shared and tissue-specific changes in specific cell populations in AF and NP during IVD degeneration. These identified mechanisms and molecules are novel and more precise targets for IDD prevention and treatment.

2024-04-05 | GSE230808 | GEO

stseranidou2024 - Nucleus Pulposus Cell Network Modelling in the Intervertebral Disc

Project description:ABSTRACT: Intervertebral disc degeneration (IDD) arises from an intricate imbalance between the anabolic and catabolic processes governing the extracellular matrix (ECM) within the disc. Biochemical processes are complex, redundant and feedback-looped, and improved integration of knowledge is needed. To addess this, a literature-based regulatory network model (RNM) for nucleus pulposus cells (NPC) is proposed, representing the normal state of the intervertebral disc (IVD), in which proteins are represented by nodes that interact among each other through activation and/or inhibition edges. This model includes 32 different proteins and 150 edges by incorporating critical biochemical interactions in IVD regulation, tested in vivo or vitro in humans’ and animals’ NPC, alongside non tissue specific protein-protein interactions. We used the network to calculate the dynamic regulation of each node through a semi-quantitative method. The basal steady state successfully represented the activity of a normal NPC, and the model was assessed through the published literature, by replicating two independent experimental studies in human normal NPC. Pro-catabolic or pro-anabolic shifts of the network activated by nodal perturbations could be predicted. Sensitivity analysis underscores the significant influence of transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) on the regulation of structural proteins and degrading enzymes within the system. Given the ongoing challenge of elucidating the mechanisms driving ECM degradation in IDD, this unique IVD RNM holds promise as a tool for exploring and predicting IDD progression, shedding light on IVD phenotypes and guiding experimental research efforts.

2024-11-04 | MODEL2407080001 | BioModels

Therapeutic potential of targeting miR-141 in intervertebral disc degeneration: first steps toward the clinic

Project description:Understanding the molecular mechanisms regulating the maintenance and destruction of intervertebral disc may lead to the development of new therapies for intervertebral disc degeneration (IDD). Here we present evidence from miRNA microarray analyses of clinical data sets along with in vitro and in vivo experiments that miR-141 is a key regulator of IDD. Gain- and loss-of-function studies show that miR-141 drives IDD by inducing nucleus pulposus (NP) apoptosis. Furthermore, miR-141 KO in mice attenuated spontaneous and surgically induced IDD. Mechanistically, miR-141 promotes IDD development by targeting and depleting SIRT1, a negative regulator of NF-κB pathway. Therapeutically, upregulation or downregulation of miR-141 by nanoparticle delivery in IDD model aggravated or alleviated experimental IDD, respectively. Our findings reveal a novel mechanism by which miR-141, in part, promotes IDD progression by interacting with SIRT1/NF-κB pathway. Blockade of miR-141 in vivo may serve as a potential therapeutic approach in the treatment of IDD.

2018-12-11 | GSE116726 | GEO

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