Krüppel like factor 10 prevents intervertebral disc degeneration via TGF-β signaling pathway both in vitro and in vivo

Wu, Tongde; Li, Xinhua; Jia, Xiaohong; Zhu, Zhaojin; Lu, Jiawei; Feng, Hao; Shen, Beiduo; Guo, Kai; Li, Yuzhi; Wang, Qiang; Gao, Zhiqiang; Yu, Bin; Ba, Zhaoyu; Huang, Yu‐Feng; Wu, Desheng

doi:10.1016/j.jot.2021.04.003

Cited by 10 publications

(11 citation statements)

References 40 publications

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“…8 F ). ( 55 ) The select downregulated genes at 6 months included Inmt , Slc7a8 , a Na + ‐independent transporter of neutral amino acids, and Ddit4 (REDD1), Adgrg6 , and Adamts1 , some of which are known to affect disc health (Fig. 8 F ).…”

Section: Resultsmentioning

confidence: 99%

Conditional Deletion of HIF-2α in Mouse Nucleus Pulposus Reduces Fibrosis and Provides Mild and Transient Protection From Age-Dependent Structural Changes in Intervertebral Disc

Johnston

Madhu

Shapiro

et al. 2020

Journal of Bone and Mineral Research

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Hypoxia‐inducible factors (HIFs) are critical to the development and homeostasis of hypoxic tissues. Although HIF‐2α, one of the main HIF‐α isoforms, is expressed in nucleus pulposus (NP) cells, its functions remain unknown. We deleted HIF‐2α in the NP tissue using a notochord‐specific FoxA2Cre allele to study HIF‐2α function in the adult intervertebral disc. Unlike observations in HIF‐1αcKO mice, fate mapping studies using Rosa26‐mTmG reporter showed that HIF‐2α loss in NP did not negatively impact cell survival or affect compartment development. Rather, loss of HIF‐2α resulted in slightly better attributes of NP morphology in 14‐month‐old HIF‐2αcKO mice as evident from lower scores of degeneration. These 14‐month‐old HIF‐2αcKO mice also exhibited significant reduction in NP tissue fibrosis and lower collagen turnover in the annulus fibrosis (AF) compartment. Imaging‐Fourier transform‐infrared (FTIR) analyses showed decreased collagen and protein content in the NP and maintained chondroitin sulfate levels in 14‐month‐old HIF‐2αcKO. Mechanistically, global transcriptomic analysis showed enrichment of differentially expressed genes with Gene Ontology (GO) terms related to metabolic processes and cell development, molecular functions concerned with histone and protein binding, and associated pathways, including oxidative stress. Noteworthy, these morphological differences were not apparent in 24‐month‐old HIF‐2αcKO, indicating that aging is the dominant factor in governing disc health. Together these data suggest that loss of HIF‐2α in the NP compartment is not detrimental to the intervertebral disc development but rather mitigates NP tissue fibrosis and offers mild but transient protection from age‐dependent early degenerative changes. © 2022 American Society for Bone and Mineral Research (ASBMR).

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Section: Resultsmentioning

confidence: 99%

Conditional Deletion of HIF-2α in Mouse Nucleus Pulposus Reduces Fibrosis and Provides Mild and Transient Protection From Age-Dependent Structural Changes in Intervertebral Disc

Johnston

Madhu

Shapiro

et al. 2020

Journal of Bone and Mineral Research

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“…To investigate the role of scutellarin in IVDD in vivo , a rat IVD needle puncture model was established, and local delivery of scutellarin was performed through intradiscal injection ( Figure 5A ) as we have previously reported ( Zhao et al, 2020 ; Wu et al, 2021 ; Yu et al, 2021 ). To detect the IVD signal, MRI-T2WI analysis was performed, which revealed higher signal intensity in the rat IVD following scutellarin treatment than in the PBS group following needle puncture, suggesting the improvement of IVDD ( Figures 5B,C ).…”

Section: Resultsmentioning

confidence: 99%

“…The needle puncture rat IVDD model is widely used for investigating IVD degeneration in vivo ( Cheng et al, 2021 ; Wu et al, 2021 ). The degenerative phenotype of IVD is displayed in this model, including alteration of disc signal in MRI, a decrease of disc height through X-ray, and loss of ECM component as well as disorganized expression of metabolic markers through histological analysis ( Zhao et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…The rats were housed under controlled identical specific pathogen-free (SPF) standard environmental conditions (23 ± 2°C, 12-h light/dark cycle) with free access to food and allowed to move freely. The IVDD model was established as previously reported ( Zhao et al, 2020 ; Wu et al, 2021 ; Yu et al, 2021 ). Briefly, 15 rats were anesthetized by intraperitoneal injection with 2% (w/v) pentobarbital (40 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

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Scutellarin Protects Against Mitochondrial Reactive Oxygen Species-Dependent NLRP3 Inflammasome Activation to Attenuate Intervertebral Disc Degeneration

Wang

Zhang

Zhao

et al. 2022

Front. Bioeng. Biotechnol.

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Intervertebral disc degeneration (IVDD) is a predominant cause of disc herniation and is widespread worldwide. Inflammatory responses, mitochondrial dysfunction, and extracellular matrix degradation are known to be involved in IVDD. Scutellarin, an active ingredient extracted from Erigeron breviscapus (Vaniot) Ha, Hand-Mazz, is reported to exhibit therapeutic potential in several degenerative diseases by suppressing inflammation and regulating metabolism. However, whether scutellarin can improve IVDD remains unknown. Human primary nucleus pulposus cells (HNPCs) were cultured and stimulated with TNF-α in the presence or absence of scutellarin. Furthermore, a rat needle puncture model was established, and scutellarin was injected into the IVD to verify its protective function against IVDD. Scutellarin attenuated the inflammatory reaction and retained the production of major IVD components both in vitro and in vivo. Mechanistically, scutellarin reduced the amount of reactive oxygen species (ROS), alleviated mitochondrial damage, and decreased the expression levels of apoptosis-related biomarkers upon stimulation with TNF-α. In addition, scutellarin antagonized the activation of the nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling pathway and the mitogen-activated protein kinase (MAPK) signaling pathway and suppressed the activity of the NLRP3 inflammasome mediated by TNF-α. This study reveals that scutellarin protects against degeneration of nucleus pulposus cells, which might shed light on treatment of IVDD in the future.

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“…We also explored the potential function of SERPINA1 in the bRNA-seq, with the expression variation of SERPINA1, the enrichments of the APOPTOSIS pathway, TGFβ pathway, MATURITY ONSET DIABETES OF THE YOUNG pathway, and GAP JUNCTION pathway change as well. These pathways have already been proven to work in the process of IDD ( Gruber et al, 2001 ; Cazzanelli and Wuertz-Kozak, 2020 ; Wu et al, 2021b ). scRNA-seq has an advantage over bRNA-seq because it has an extracellular dimension.…”

Section: Discussionmentioning

confidence: 99%

Integrated proteome sequencing, bulk RNA sequencing and single-cell RNA sequencing to identify potential biomarkers in different grades of intervertebral disc degeneration

Yang

Zhou

et al. 2023

Front. Cell Dev. Biol.

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Low back pain (LBP) is a prevalent health problem worldwide that affects over 80% of adults during their lifetime. Intervertebral disc degeneration (IDD) is a well-recognized leading cause of LBP. IDD is classified into five grades according to the Pfirrmann classification system. The purpose of this study was to identify potential biomarkers in different IDD grades through an integrated analysis of proteome sequencing (PRO-seq), bulk RNA sequencing (bRNA-seq) and single-cell RNA sequencing (scRNA-seq) data. Eight cases of grade I-IV IDD were obtained. Grades I and II were considered non-degenerative discs (relatively normal), whereas grades III and IV were considered degenerative discs. PRO-seq analysis was performed to identify differentially expressed proteins (DEPs) in various IDD grades. Variation analysis was performed on bRNA-seq data to differentiate expressed genes (DEGs) in normal and degenerated discs. In addition, scRNA-seq was performed to validate DEGs in degenerated and non-degenerated nucleus pulposus (NP). Machine learning (ML) algorithms were used to screen hub genes. The receiver operating characteristic (ROC) curve was used to validate the efficiency of the screened hub genes to predict IDD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze function enrichment and signaling pathways. Protein-protein interaction (PPI) network was used to prioritize disease-related proteins. SERPINA1, ORM2, FGG and COL1A1 were identified through PRO-seq as the hub proteins involved in regulating IDD. ML algorithms selected ten hub genes, including IBSP, COL6A2, MMP2, SERPINA1, ACAN, FBLN7, LAMB2, TTLL7, COL9A3, and THBS4 in bRNA-seq. Since serine protease inhibitor clade A member 1 (SERPINA1) was the only common gene, its accuracy in degenerated and non-degenerated NP cells was validated using scRNA-seq. Then, the rat degeneration model of caudal vertebra was established. The expression of SERPINA1 and ORM2 was detected using immunohistochemical staining of human and rat intervertebral discs. The results showed that SERPINA1 was poorly expressed in the degenerative group. We further explored the potential function of SERPINA1 by Gene Set Enrichment Analysis (GSEA) and cell-cell communication. Therefore, SERPINA1 can be used as a biomarker to regulate or predict the progress of disc degeneration.

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Krüppel like factor 10 prevents intervertebral disc degeneration via TGF-β signaling pathway both in vitro and in vivo

Cited by 10 publications

References 40 publications

Conditional Deletion of HIF-2α in Mouse Nucleus Pulposus Reduces Fibrosis and Provides Mild and Transient Protection From Age-Dependent Structural Changes in Intervertebral Disc

Conditional Deletion of HIF-2α in Mouse Nucleus Pulposus Reduces Fibrosis and Provides Mild and Transient Protection From Age-Dependent Structural Changes in Intervertebral Disc

Scutellarin Protects Against Mitochondrial Reactive Oxygen Species-Dependent NLRP3 Inflammasome Activation to Attenuate Intervertebral Disc Degeneration

Integrated proteome sequencing, bulk RNA sequencing and single-cell RNA sequencing to identify potential biomarkers in different grades of intervertebral disc degeneration

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