Inflammatory and catabolic signalling in intervertebral discs: The roles of NF-B and MAP Kinases

Wuertz, Karin; Vo, Nam; Kletsas, Dimitris; Boos, Norbert

doi:10.22203/ecm.v023a08

Cited by 199 publications

(209 citation statements)

References 141 publications

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“…Furthermore, phosphorylation of NF-B is sustained (Ͼ30 min), which agrees with other studies that have found prolonged NF-B activation in NP and AF cells (46,47). For other pathologies, both p38 (rheumatoid arthritis) and NF-B (atopic dermatitis) inhibitors have gone to clinical trials (45). If successful, these inhibitors may also positively affect disc degeneration.…”

Section: Tlr2 Regulates Ngf Via Nf-bsupporting

confidence: 88%

“…As expected, the downstream signal mechanisms are similar and include the NF-B pathway and p38, ERK1/2, and JNK MAP kinase signaling, which can cause a variety of transcription factors to translocate to the nucleus (10,30). Activation of these pathways in discs results in an increase in inflammatory mediators and proteases (45). Although signaling mechanisms of TLR2 have been extensively investigated in other cell types, they are only now being elucidated in intervertebral disc.…”

Section: Tlr2 Regulates Ngf Via Nf-bmentioning

confidence: 58%

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Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Krock

Currie

Weber

et al. 2016

Journal of Biological Chemistry

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Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1␤ (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1␤ gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1␤ treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-B, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-B signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-B inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

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Section: Tlr2 Regulates Ngf Via Nf-bsupporting

confidence: 88%

Section: Tlr2 Regulates Ngf Via Nf-bmentioning

confidence: 58%

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Krock

Currie

Weber

et al. 2016

Journal of Biological Chemistry

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“…Inappropriate activation of NFKB has been associated with numerous inflammatory diseases (30). Wuertz et al (32) have reported that IDD is characterized not only by an imbalance between anabolic and catabolic processes, but also by inflammatory mechanisms. Of note, IL-1β and TNF-α are pro-inflammatory cytokines, which have been detected in the degenerated disc (33).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of molecular mechanisms involved in intervertebral disc degeneration induced by TNF-α and IL-1β

Fang

Gao

et al. 2016

Molecular Medicine Reports

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Abstract. The present study aimed to explore the molecular mechanisms associated with intervertebral disc degeneration (IDD) induced by tumor necrosis factor (TNF)-α and interleukin (IL)-1β. The microarray dataset no. GSE42611 was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between four experimental nucleus pulposus samples and four control nucleus pulposus samples were analyzed. Subsequently, Gene Ontology (GO) and pathway enrichment analyses of DEGs were performed, followed by protein-protein interaction (PPI) network construction and prediction of a regulatory network of transcription factor (TFs). Finally, the transcriptional regulatory network was integrated into the PPI network to analyze the network modules. A total of 246 upregulated and 290 downregulated DEGs were identified. The upregulated DEGs were mainly associated with GO terms linked with inflammatory response and apoptotic pathways, while the downregulated DEGs were mainly associated with GO terms linked with cell adhesion and pathways of extracellular matrix -receptor interaction. In the PPI network, IL6, COL1A1, NFKB1 and HIF1A were hub genes, and in addition, NFKB1 and HIF1A were TFs. Pathways of apoptosis and extracellular matrix -receptor interaction may have important roles in IDD progression. IL6, COL1A1 and the TFs NFKB1 and HIF1A may be used as biomarkers for IDD diagnosis and treatment. IntroductionIntervertebral discs lie between adjacent vertebrae in the spine, forming a fibrocartilaginous joint to allow slight movement of the vertebrae (1). The layers of fibrocartilage contain the nucleus pulposus, which functions as a shock absorber dissipating compressive forces outward from its center to the surrounding annulus fibrosus (2). However, the anulus fibrosus becomes weaker with increasing age (3), resulting in intervertebral disc degeneration (IDD). Beyond age 40, >60% of individuals show symptoms of IDD; furthermore, IDD is the most common cause of disability among workers aged 18-64 years (4). IDD is characterized by decreases in intervertebral disc function and height due to cell loss through apoptosis, increased breakdown of matrix or altered matrix synthesis, with the underlying pathological processes being complex (5-7).Numerous studies have intended to explore the molecular mechanisms involved in IDD. Vo et al (4) reported that IDD was a consequence of increased catabolism of the extracellular matrix (ECM), since the proteolytic degradation of ECM macromolecules led to marked structural changes of the intervertebral disc. These catabolic processes are mediated by a number of cytokines in the nucleus pulposus, among which interleukin (IL)-1β and tumor necrosis factor (TNF)-α have been suggested to have crucial roles in the development of IDD. However, the involvement of IL-1β and TNF-α in IDD has remained to be fully elucidated.Markova et al (8) cultured rat intervertebral discs in the presence of IL-1β, TNF-α and serum-limiting conditions to mimic a degenerative insult to ident...

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“…This is explained by the fact that pain perception comprises a complex series of neurophysiologic events involving stimulation, tissue response, transmission of pain signal and subsequent modulation of these at both peripheral and central levels (Ito and Creemers, 2013;Schaible, 2012). Inflammatory cytokines are important regulators of these pain mechanisms and their presence is associated with inflammatory pain arising from articular joints and IVDs (Ito and Creemers, 2013;Wuertz et al, 2012;Zhang et al, 2013). Interleukin-1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α) contribute to disease progression and pain, by acting directly not only as nociceptive triggers, but also by inducing generation of other potentially nociceptive molecules, including nitric oxide and prostaglandin E (Liu et al, 2016;.…”

Section: Trpml2 -/-mentioning

confidence: 99%

The role of transient receptor potential channels in joint diseases

Krupková

Zvick²,

Wuertz‐Kozak³

2017

eCM

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Transient receptor potential channels (TRP channels) are cation selective transmembrane receptors with diverse structures, activation mechanisms and physiological functions. TRP channels act as cellular sensors for a plethora of stimuli, including temperature, membrane voltage, oxidative stress, mechanical stimuli, pH and endogenous as well as exogenous ligands, thereby illustrating their versatility. As such, TRP channels regulate various functions in both excitable and non-excitable cells, mainly by mediating Ca 2+ homeostasis. Dysregulation of TRP channels is implicated in many pathologies, including cardiovascular diseases, muscular dystrophies and hyperalgesia. However, the importance of TRP channel expression, physiological function and regulation in chondrocytes and intervertebral disc (IVD) cells is largely unexplored. Osteoarthritis (OA) and degenerative disc disease (DDD) are chronic age-related disorders that significantly affect the quality of life by causing pain, activity limitation and disability. Furthermore, currently available therapies cannot effectively slow-down or stop progression of these diseases. Both OA and DDD are characterised by reduced tissue cellularity, enhanced inflammatory responses and molecular, structural and mechanical alterations of the extracellular matrix, hence affecting load distribution and reducing joint flexibility. However, knowledge on how chondrocytes and IVD cells sense their microenvironment and respond to its changes is still limited. In this review, we introduced six families of mammalian TRP channels, their mechanisms of activation as well as activation-driven cellular consequences. We summarised the current knowledge on TRP channel expression and activity in chondrocytes and IVD cells and the significance of TRP channels as therapeutic targets for the treatment of OA and DDD.

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Inflammatory and catabolic signalling in intervertebral discs: The roles of NF-B and MAP Kinases

Cited by 199 publications

References 141 publications

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Bioinformatics analysis of molecular mechanisms involved in intervertebral disc degeneration induced by TNF-α and IL-1β

The role of transient receptor potential channels in joint diseases

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