IL‐6/YAP1/β‐catenin signaling is involved in intervertebral disc degeneration

Chen, Jian; Mei, Zheng-Feng; Huang, Bao; Zhang, Xuyang; Liu, Junhui; Shan, Zhi; Wang, Jiasheng; Wang, Xianjun; Zhao, Fengdong

doi:10.1002/jcp.27065

Cited by 49 publications

(40 citation statements)

References 31 publications

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“…IL-6 rs1800795 and rs1800797 polymorphisms, located within regulatory regions, could be part of RNAbinding protein site and could be involved in RNAbinding which is protein-mediated. Previous studies showed that IL-6 significantly induced disc degeneration by activating STAT3 and β-catenin signaling pathways [30,34]. It seems to indicate that IL-6 might act synergistically with other genetic factors contributing to the risk of disc degeneration.…”

Section: Discussionmentioning

confidence: 94%

Gene polymorphisms and expression levels of interleukin-6 and interleukin-10 in lumbar disc disease: a meta-analysis and immunohistochemical study

Guan

Wang

et al. 2020

J Orthop Surg Res

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Background: To investigate the association between interleukin-6 (IL-6) (rs1800795, rs1800796, rs1800797, rs13306435, rs2069849) and interleukin-10 (IL-10) (rs1800871, rs1800896) gene polymorphisms, expression levels, and lumbar disc disease (LDD). Methods: We conducted a literature research on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) until February 28, 2019. We included all case-control studies about the association between IL-6 and IL-10 gene polymorphisms and LDD. The odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the strength of association. Statistical analysis was conducted by Review Manager (RevMan) 5.3 software. Furthermore, immunohistochemistry (IHC) and RT-PCR were performed to evaluate IL-6 and IL-10 expressions in the normal and degenerated disc. Results: A total of 6 studies, involving 1456 cases and 1611 controls, were included in this meta-analysis. G alleles of rs1800795 and rs1800797 in the IL-6 gene were significantly associated with LDD (rs1800795: G vs. C, OR = 1.38, 95% CI = 1.16-1.64, P = 0.0002; rs1800797: G vs. A, OR = 1.35, 95% CI = 1.14-1.61, P = 0.0006). Begg's funnel plot and Egger's tests did not show any evidence of publication bias. IL-6 expression and IL-6 mRNA levels were significantly increased in the degenerated disc compared with those in the normal disc (IL-6 immunopositive cells, 73.68 ± 10.99% vs. 37.23 ± 6.42%, P < 0.001). Conclusions: IL-6 gene polymorphisms (rs1800795 and rs1800797) were significantly associated with susceptibility to LDD. A high expression level of IL-6 may be an important risk factor for LDD.

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Section: Discussionmentioning

confidence: 94%

Gene polymorphisms and expression levels of interleukin-6 and interleukin-10 in lumbar disc disease: a meta-analysis and immunohistochemical study

Guan

Wang

et al. 2020

J Orthop Surg Res

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“…One study in dogs showed an upregulation in the gene expression of IL-8 and downregulation in the gene expression of IL-6 during IVDD (11). Increased levels of IL-6 and IL-8 in IVD in humans correlate with degeneration and inflammation within the IVD (36,(43)(44)(45)(46). Aside from its catabolic effects on NP cells, IL-6 is also involved in the development of pain during the course of IVDD (47).…”

Section: Discussionmentioning

confidence: 99%

Fibronectin Fragments and Inflammation During Canine Intervertebral Disc Disease

et al. 2020

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Background: Canine intervertebral disc disease (IVDD) represents a significant clinical problem in veterinary medicine, with similarities to the human pathology. Host-derived damage-associated molecular patterns like fibronectin fragments (FnF) that develop during tissue dysfunction may be of specific relevance to IVD pathologies by inducing an inflammatory response in resident cells. Aim: This project aimed to determine the presence and pathobiological role of FnF during IVD herniation in dogs, with a focus on inflammation. Methods: Herniated nucleus pulposus (NP) material from five dogs as well as non-herniated adjacent NP material from three dogs was collected during spinal surgery required due to acute IVD herniation. The presence of different types of FnF were determined by Western blot analysis. NP cells isolated from six herniated canine IVDs were then exposed to 30 kDa FnF. NP cell inflammation and catabolism was examined by investigating the expression of IL-1β, IL-6, IL-8, and COX-2, as well as MMP-1 and MMP-3 by qPCR (all targets) and ELISA (IL-6, PGE 2 ). Results: Amongst multiple sized FnF (30, 35, 45, and >170kDa), N-terminal fragments at a size of ~30 kDa were most consistently expressed in all five herniated IVDs. Importantly, these fragments were exclusively present in herniated, but not in non-herniated IVDs. Exposure of canine NP cells to 500 nM 30 kDa FnF caused a significant upregulation of IL-6 (62.5 ± 79.9, p = 0.032) and IL-8 (53.0 ± 75.7, p = 0.031) on the gene level, whereas IL-6 protein analysis was inconclusive. Donor-donor variation was observed in response to FnF treatment, whereby this phenomenon was most evident for COX-2, with three donors demonstrating a significant downregulation (0.67 ± 0.03, p = 0.003) and three donors showing upregulation (6.9 ± 5.5, p = 0.21). Co-treatment with Sparstolonin B, a TRL-2/TRL-4 antagonist, showed no statistical difference to FnF treatment alone in all tested target genes. Conclusion: Given the presence of the 30 kDa FnF in canine herniated IVDs and the proinflammatory effect of 30 kDa FnF on NP cells, we concluded that the accumulation of FnF may be involved in the pathogenesis of canine IVDD. These results correspond to the findings in humans with IVDD.

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“…Inside the nucleus, YAP/TAZ has been reported to act as a transcriptional coactivator for a multitude of proteins. YAP/TAZ interacts with additional DNA‐binding coactivators like TEADs, tumor protein p73, SMADs, FOXO proteins, T‐box transcription factor 5, RUNT‐related transcription factors (RUNX1, 2), and some other factors to regulate a diverse range of target gene expressions and thus diverse cellular responses (Boopathy & Hong, ; Chen et al, ; Fallahi et al, ). TEAD is one of the most studied transcriptional regulators that associate with YAP/TAZ.…”

Section: Overview Of the Hippo Signaling Networkmentioning

confidence: 99%

The emerging role of Hippo signaling in neurodegeneration

Sahu

Mondal

2019

J of Neuroscience Research

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Neurodegeneration refers to the complex process of progressive degeneration or neuronal apoptosis leading to a set of incurable and debilitating conditions. Physiologically, apoptosis is important in proper growth and development. However, aberrant and unrestricted apoptosis can lead to a variety of degenerative conditions including neurodegenerative diseases. Although dysregulated apoptosis has been implicated in various neurodegenerative disorders, the triggers and molecular mechanisms underlying such untimely and faulty apoptosis are still unknown. Hippo signaling pathway is one such apoptosis‐regulating mechanism that has remained evolutionarily conserved from Drosophila to mammals. This pathway has gained a lot of attention for its tumor‐suppressing task, but recent studies have emphasized the soaring role of this pathway in inflaming neurodegeneration. In addition, strategies promoting inactivation of this pathway have aided in the rescue of neurons from anomalous apoptosis. So, a thorough understanding of the relationship between the Hippo pathway and neurodegeneration may serve as a guide for the development of therapy for various degenerative diseases. The current review focuses on the mechanism of the Hippo signaling pathway, its upstream and downstream regulatory molecules, and its role in the genesis of numerous neurodegenerative diseases. The recent efforts employing the Hippo pathway components as targets for checking neurodegeneration have also been highlighted.

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IL‐6/YAP1/β‐catenin signaling is involved in intervertebral disc degeneration

Cited by 49 publications

References 31 publications

Gene polymorphisms and expression levels of interleukin-6 and interleukin-10 in lumbar disc disease: a meta-analysis and immunohistochemical study

Gene polymorphisms and expression levels of interleukin-6 and interleukin-10 in lumbar disc disease: a meta-analysis and immunohistochemical study

Fibronectin Fragments and Inflammation During Canine Intervertebral Disc Disease

The emerging role of Hippo signaling in neurodegeneration

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