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Exercise accelerated the degeneration of lumbar IVDs from surgical lumbar instability, similar to the clinical degeneration process

ABSTRACT: Given the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socio-economic challenge to the aging population, which is importantly attributed to intervertebral disc degeneration (IVDD), a highly prevalent affliction of aging. Elastic nucleus pulposus (NP) tissue is essential for maintenance of IVD structural and functional integrity. Native NP cells exhibit crucial functions for regulating extracellular matrix homeostasis, constructing an accommodating biomechanical environment and maintaining the gelatinous property of NP tissue. Mechanical stresses, including compulsion position and aberrant mechanical loading, are regarded as etiological factors of IVDD, and to further investigate the effect of mechanical exercise during the degeneration of IVDs, we surgically resected the lumbar 4th-lumbar 5th (L4-L5) spinous processes of the rat spine along with the supraspinous and interspinous ligaments to induce lumbar surgical instability (LSI). Additionally, we applied RNA sequencing technology to describe the degeneration-associated molecular atlas of the LSI model during exercise, and found that exercise accelerated the degenerative process of IVDs from LSI, which is involved in cytosolic DNA sensing-mediated inflammatory activation, similar to the degenerative patterns of the clinical IVDD process.

ORGANISM(S): Rattus norvegicus Homo sapiens

PROVIDER: GSE266883 | GEO | 2024/07/17

REPOSITORIES: GEO

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Exercise accelerated the degeneration of lumbar IVDs from surgical lumbar instability, similar to the clinical degeneration process

Project description:Exercise accelerated the degeneration of lumbar IVDs from surgical lumbar instability, similar to the clinical degeneration process

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Project description:Nucleus pulposus (NP) plays a vital role in intervertebral disc degeneration (IVDD). Previous studies have revealed cellular heterogeneity in the NP tissue during IVDD progression. Here, we used single cell RNA sequencing (scRNA-seq) to analyze the cellular and molecular alterations of diverse cell clusters during IVDD.

2024-11-14 | GSE251686 | GEO

Differential Proteomic Analysis of Fetal and Geriatric Lumbar Nucleus Pulposus

Project description:Intervertebral disc degeneration (IVDD) is a main cause of degenerative disc disease, which results in substantial pain among patients. However, the mechanism of degeneration remains unclear. Thus far, basic research on human IVDD has focused on only a limited number of proteins and has not been conducted from a holistic perspective. In this study, we used tandem mass tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to perform differential proteomic analysis on fetal and geriatric lumbar disc nucleus pulposus tissue. These data indicate that differential proteomics analysis may be an important method for elucidation of the pathophysiological process and molecular biological mechanism of human IVDD from a holistic perspective. The findings in this study will aid in screening of new biomarkers for early diagnosis and targeted treatment of IVDD.

2020-05-02 | PXD015000 |

N6-methyladenosine circRNA Epitranscriptomic Microarray of human nucleus pulposus in intervertebral disc degeneration

Project description:It is well documented that low back pain is a common condition and the leading cause of disability globally. A widely recognised contributor to low back pain is intervertebral disc degeneration (IVDD), which is the major cause of a series of degenerative disc diseases. Recently, it has been reported that circRNAs are involved in the development of IVDD. However, the mechanisms by which m6A modifies circRNA in nucleus pulposus cells remain poorly understood. Here, we aim to identify differentially expressed m6A circRNAs in degenerative nucleus pulposus cells and figure out how the circRNAs regulate IVDD progression and the m6A methylation functions.

2023-08-21 | GSE199993 | GEO

Single-cell transcriptome profiling reveals nucleus pulposus heterogeneity and immunity during degeneration progression

Project description:The heterogeneity of nucleus pulposus cells (NPCs) and the molecular mechanisms underlying NP degeneration is still unclear. We performed unbiased transcriptome-wide single-cell RNA sequencing (scRNA-seq) on progressing degenerative grades of human NP. Cell subsets, their gene signatures, differentiation trajectory, and cell interactions were determined and characterized.We uncover seven populations of human NP cells and referred to these novel cell clusters with markers and their distinct functions. Monocle pseudospace, cytoTRACE, and scVelo analysis showed potential transition among cell subsets. We revealed novel markers for NP progenitors (NPPs), and found a close relationship between NPPs and fibrosis NP (FNPs). Neutrophils showed heterogeneity, which may be a resultsresult of activation and maturation. Identified granulocytic myeloid-derived suppressor cells (G- MDSCs) are correlated with disease progression. CD11b, OLR1, and CD24 were shown to be the markers in NP-derived G-MDSCs.Our study revealing NPCs type complexity and phenotypic characteristics of immune cells inside NP, providing new insights and clues for treatment of IVDD.

2021-12-26 | GSE165722 | GEO

Genome-wide DNA methylation profile analysis of human intervertebral disc degeneration

Project description:The pathophysiology of intervertebral disc (IVD) degeneration is not entirely understood; however, environmental and endogenous factors under genetic predisposition are considered to initiate the degenerative changes of human IVDs. Aberrant epigenetic alterations play a pivotal role in several diseases, including osteoarthritis. However, epigenetic alternations, including DNA methylation, in IVD degeneration have not been evaluated. The purpose of this study was to comprehensively compare the genome-wide DNA methylation profiles of human IVD tissues, specifically nucleus pulpous (NP) tissues, with early and advanced stages of disc degeneration. We conducted, for the first time, a genome-wide DNA methylation profile comparative study and observed significant differences in DNA methylation profiles between early and advanced stages of human IVD degeneration. The overview of the DNA methylation profile in the current study revealed that differentially methylated loci were identified in many genes associated with known molecules that have been reported to be relevant to IVD degeneration. Importantly, changes in DNA methylation profiles were also found in genes 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 human disc degeneration.

2019-10-01 | GSE129789 | GEO

Single Cell RNA-Sequence Analyses Reveal Uniquely Expressed Genes and Heterogeneous Immune Cell Involvement in the Rat Model of Intervertebral Disc Degeneration

Project description:Purpose: We used single-cell RNA-sequencing analysis of degenerating tissues of the rat IVD following lumbar disc puncture Methods: Two control, uninjured IVDs (L2-3, L3-4) and two degenerated, injured IVDs (L4-5, L5-6) from each animal were examined either at the two- or eight-week post-operative time points. The cells from these IVDs were extracted and transcriptionally profiled at the single-cell resolution Results: Unsupervised cluster analysis revealed the presence of four known cell types in both non-degenerative and degenerated IVDs based on previously established gene markers: IVD cells, endothelial cells, myeloid cells, and lymphoid cells. As a majority of cells were associated with the IVD cell cluster, sub-clustering was used to further identify the cell populations of the nucleus pulposus, inner and outer annulus fibrosus Conclusions: . Differential gene expression analysis revealed multiple distinct cell types from the myeloid and lymphoid lineages, most notably macrophages and B lymphocytes, and demonstrated a high degree of immune specificity during degeneration. In addition to the heterogenous infiltrating immune cell populations in the degenerating IVD, the increased number of cells in the AF sub-cluster expressing Ngf and Ngfr, encoding for p75NTR, suggest that NGF signaling may be one of the key mediators of the IVD crosstalk between immune and neuronal cell populations

2022-08-19 | GSE211407 | GEO

Single-cell RNA-seq analysis reveals that immune cells induce human nucleus pulposus ossification and degeneration

Project description:Background and aims Determining the transcriptomes and molecular mechanism underlying human degenerative nucleus pulposus (NP) is of critical importance for treating intervertebral disc degeneration (IDD). Here, we aimed to elucidate the detailed molecular mechanism of NP ossification and IDD using single-cell RNA sequencing. Methods Single-cell RNA-seq and bioinformatic analysis were performed to identify NP cell populations with gene signatures, biological processes and pathways, and subpopulation analysis, RNA velocity analysis, and cell-to-cell communication analysis were performed in four IDD patients. We also verified the effects of immune cells on NP ossification using cultured NP cells and a well-established rat IDD model. Results We identified five cell populations with gene expression profiles in degenerative NP at single-cell resolution. GO database analysis showed that degenerative NP-associated genes were mainly enriched in extracellular matrix organization, immune response, and ossification. Gene set enrichment analysis showed that rheumatoid arthritis signaling, antigen processing and presentation signaling were activated in the blood cell cluster. We revealed that stromal cells, which are progenitor cells, differentiated toward an ossification phenotype and delineated interactions between immune cells (macrophages and T cells) and stromal cells. Immune factors such as TNF-α, CD74 and CCL-3 promoted the differentiation of stromal cells toward an ossification phenotype in vitro. Blocking TNF-α with a specific inhibitor successfully reversed NP ossification and modified NP morphology in vivo. Conclusions Our study revealed an increase in macrophages and T cells in degenerative NP, which induced stromal cell differentiation toward an ossification phenotype, and contributed to the identification of a novel therapeutic target to delay IDD.

2023-06-01 | GSE233666 | GEO

Dissecting inflammatory response in intervertebral disc degeneration: triggering of CD44 by IL-1beta

Project description:Objectives/Design: Intervertebral Disc (IVD) degeneration has been associated with a chronic inflammatory response, but knowledge on the contribution of distinct IVD cells, namely CD44, to the progression of IVD degeneration remains elusive. Material: Bovine nucleus pulposus (NP) cells. Treatment: Stimulation with IL-1beta (10ng/ml). Methods: CD44 NP cells were sorted and compared by gene expression and proteomics with the negative counterpart. Dynamics of CD44 gene and protein expression was analyzed upon pro-inflammatory treatment. Results: CD44 has a multidimensional functional role in IVD metabolism, ECM synthesis and production of neuropermissive factors. CD44 widespread expression in NP has been partially associated with CD14 and CD45, resulting in the identification of distinct cell subsets. Conclusions: This study points out CD44 and CD44-based cell subsets as relevant targets in the modulation of the IVD pro-inflammatory/degenerative cascade.

2024-05-22 | PXD048373 | Pride

cGAS-STING axis activation drove inflammatory phenotype acquisition of senescent nucleus pulposus cells via p65-mediated transcriptional modulation

Project description:Given the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socio-economic challenge to the aging population, which is importantly attributed to intervertebral disc degeneration (IVDD), a highly prevalent affliction of aging. Elastic nucleus pulposus (NP) tissue is essential for maintenance of IVD structural and functional integrity. Native NP cells exhibit crucial functions for regulating extracellular matrix homeostasis, constructing an accommodating biomechanical environment and maintaining the gelatinous property of NP tissue. The accumulation of senescent NP cells with inflammatory hypersecretory phenotype due to aging and other damaged factors is a distinctive hallmark of IVDD initiation and progression. In this study, we revealed a mechanism of IVDD progression in which aberrant genomic DNA damage promotes NP cell inflammatory senescence via activation of cGAS-STING axis. cGAS-STING axis activation drove inflammatory phenotype acquisition and inflammatory hypersensitivity to damaged signals of senescent NP cells via p65-mediated transcriptional modulation. And STING pharmacological inhibitor notably suppressed p65-mediated inflammatory response formation and senescence-associated screctory phenotype (SASP) acquisition of senescent cells.

2024-03-20 | GSE244403 | GEO

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