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

ABSTRACT: 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. Using a tandem mass tag (TMT)-based quantitative proteomics approach, we characterized the proteomes and phosphoproteomes of rat nucleus pulposus cells (NPCs) treated with Bmal1 shRNA or its negative control lentivirus.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Jinghui Huang

PROVIDER: PXD029273 | iProX | Thu Oct 21 00:00:00 BST 2021

REPOSITORIES: iProX

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Hsa-let-7f-1-3p targeting the circadian gene Bmal1 mediates intervertebral disc degeneration by regulating autophagy.

Mei Liangwei L Zheng Yi Y Gao Xue X Ma Teng T Xia Bing B Hao Yiming Y Wei Bin B Wei Yitao Y Luo Zhuojing Z Huang Jinghui J

Pharmacological research 20221102

The intervertebral disc has an intrinsic circadian rhythm, elimination of which leads to stress in nucleus pulposus cells (NPCs), contributing to intervertebral disc degeneration (IDD). Disruption or deletion of Bmal1 (a core transcription factor) results in complete loss of circadian rhythms, make mice susceptibility to IDD. However, the underlying mechanism by which Bmal1 mediates IDD is remains enigmatic, and whether there are other upstream factors regulating Bmal1 in NPCs. In our study, we ...[more]

PMID: 36334875

Similar Datasets

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

CRLF1 involves in intervertebral disc degeneration via exacerbating extracellular matrix degradation and nucleus pulposus cells senescence

Project description:Low back pain (LBP) is one of the most common musculoskeletal disorders with a huge global impact. Intervertebral disc degeneration (IVDD) is an important cause of low back pain. Therefore, it is crucial to identify and elucidate the key factors affecting IVDD. We identified CRLF1, a key molecule in the process of IVDD, by Gene Expression Omnibus dataset, and determined the high expression of CRLF1 within the degenerated discs and in senescent NPCs by IHC, WB. To further explore the effect of CRLF1 on NPCs, we applied RNA-seq to explore the phenotypic changes of NPCs treated with CRLF1.

2024-11-30 | GSE267519 | GEO

Gene expression profile at single cell level of nucleus pulposus cells (NPCs) from the nucleus pulposus (NP) tissue in the mild degenerative intervertebral discs (MDD) and server degenerative intervertebral discs(SDD).

Project description:It has been shown that the divergence of NPCs plays an important role in the progression of intervertebral disc degeneration (IVDD). We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of NPCs in the IVDD.

2023-10-30 | GSE244889 | GEO

The clock transcription factor BMAL1 is a key regulator of extracellular matrix homeostasis and cell fate in the intervertebral disc

Project description:The circadian clock in mammals temporally coordinates physiological and behavioural processes to anticipate daily rhythmic changes in their environment. Chronic disruption to circadian rhythms (e.g., through ageing or shift work) is thought to contribute to a multitude of diseases, including degeneration of the musculoskeletal system. The intervertebral disc (IVD) in the spine contains circadian clocks which control ~6% of the transcriptome in a rhythmic manner, including key genes involved in extracellular matrix (ECM) homeostasis. However, it remains largely unknown to what extent the local IVD molecular clock is required to drive rhythmic gene transcription and IVD physiology. In this work, we identified profound age-related changes of ECM microarchitecture and an endochondral ossification-like phenotype in the annulus fibrosus (AF) region of the IVD in the Col2a1-Bmal1 knockout mice. Reported here is the circadian time series RNA-Seq of the whole IVD in Bmal1 knockout mice.

2023-08-17 | E-MTAB-13083 | biostudies-arrayexpress

Intracellular differential gene expression detected by transcriptome sequencing after lactate treatment of nucleus pulposus cells

Project description:The accumulation of metabolites in the intervertebral disc is regarded as an important inducement of intervertebral disc degeneration (IVDD). Lactate, a metabolite produced by the cellular anaerobic glycolysis process, has been proved to be closely associated with IVDD. However, little was known about the role of lactate in nucleus pulposus cells (NPCs) senescence. This study attempted to investigate the effect and molecular mechanism of lactate on NPCs senescence in vitro and in vivo. A puncture-induced disc degeneration model was established in rats. Metabolomics analysis proved that lactate was significantly increased in the rat degenerated intervertebral disc. Eliminating extra lactate using lactate oxidase (LOx)-overexpressing lentivirus alleviated the progression of IVDD. In vitro experiments showed that high concentration lactate could induce senescence and oxidative stress in NPCs. High-throughput RNA sequencing (RNA-seq) results and bioinformatic analysis exhibited that lactate-stimulated NPCs senescence may be related to the PI3K/Akt signaling pathway. Further study verified that high concentration lactate could induce NPCs senescence and oxidative stress via inhibiting PI3K/Akt signaling and downstream Akt/p21/p27/cyclinD1 and Akt/Nrf2/HO-1 pathway. Utilizing molecular docking, we found that lactate may suppress the Akt phosphoactivation via binding to Lys39 and Leu52 in the PH domain of Akt. In conclusion, this study illuminates that lactate could promote the senescence of NPCs to aggravate IVDD by suppressing the PI3K/Akt signaling pathway and the expression of its downstream genes. These results highlight the involvement of lactate NPCs senescence, which may become a novel potential therapeutic target for the treatment of IVDD.

2022-12-06 | GSE219145 | GEO

Lactylation of nucleus pulposus cells

Project description:Nucleus pulposus (NP) resides in hypoxic microenvironment due to the avascular structure of intervertebral disc (IVD). Intracellular lactate drives lysine lactylation (Kla) as a newly epigenetic modification. However, the impact of Kla on NPCs remains unknown. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we showed a global lactylome profiling on NPCs cultured in normoxia and hypoxia environment and found that 3510 lactylation sites on 1052 proteins in NPCs on non-histone proteins. Moreover, there are 18 proteins with 129 Kla sites exclusively detected in the normoxia group, and 117 Kla sites in 27 proteins were specific in hypoxia group. Together, our dates reveals that Kla plays an important role in regulating cellular metabolism and may contribute to IDD progression.

2025-05-06 | PXD048244 | Pride

Tagln+ progenitors contribute to the development and maintenance of nucleus pulposus

Project description:Failure of intervertebral disc components, e.g. the nucleus pulposus causes intervertebral disc disease and associated low-back pain. Despite the high prevalence of disc disease, the changes in intervertebral disc cells and their regenerative potential with ageing and degeneration are not fully elucidated. Understanding the cell lineage, cell differentiation and maintenance of nucleus pulposus may have therapeutic application for the regeneration of degenerative disc, with significant impact for healthy ageing. Here we found that TAGLN expressing cells are present in human healthy nucleus pulposus, but diminish in degenerative disc. By lineage analyses in mice, we found cells in the nucleus pulposus are derived from a peripherally located population of notochord-derived Tagln expressing cells (PeriNP cells). The PeriNP cells are proliferative and can differentiate into the inner part of the nucleus pulposus. The Tagln+ cells and descendants diminish during aging and puncture induced disc degeneration. The maintenance and differentiation of PeriNP cells is partially regulated by Smad4 dependent signaling. Removal of Smad4 by nucleus pulposus specific Cre (Foxa2mNE-Cre), results in decreased Tagln+ cells and abnormal disc morphology, leading to disc degeneration. Our findings propose that the PeriNP Tagln expressing cells are a pool of notochord-derived progenitors that are important for maintenance of the nucleus pulposus and provide insights for regenerative therapy against intervertebral disc degeneration.

2024-05-14 | GSE186549 | GEO

RNAseq analyses of nucleus pulposus cells treated with control siRNA and LINC02569 siRNA

Project description:Nucleus pulposus cells (NPCs) were used to examine the effect of LINC02569, a novel lncRNA. In particular, its effect in intervertebral disc degeneration was determined. Treatment of LINC02569 siRNA (si-02569) was to be compared with negative control siRNA (si-NC).

2022-02-08 | GSE185668 | GEO

Proteomic Signature of Nucleus Pulposus of Human Intervertebral Disc

Project description:Intervertebral Disc (IVD) degeneration leading to Low back pain (LBP) is the most common musculoskeletal disorder. Lack of knowledge on the intricate homeostatic mechanisms necessitates proteomic characterisation of a normal human IVD to understand the biological process and unravel the pathomechanisms of degenerative disc disease (DDD). In this study, we employed proteomic approach coupled with tandem mass-spectrometry to derive the comprehensive list of proteins expressed in true biologically normal control discs. This would serve as the basis for identifying the interacting molecules participating in significant biological processes and pathways disrupted during aging and degeneration.

2021-09-09 | PXD016560 | Pride

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

Project description: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.

2024-03-20 | GSE226186 | GEO

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