NF-κB Signaling Pathway in Controlling Intervertebral Disk Cell Response to Inflammatory and Mechanical Stressors

Tisherman, Robert; Coelho, Paulo; Phillibert, David; Wang, Dong; Dong, Qing; Vo, Nam; Kang, James D.; Sowa, Gwendolyn

doi:10.2522/ptj.20150045

Cited by 26 publications

(30 citation statements)

References 35 publications

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“…We and others have found an effect of substrate stiffness on mechanobiology in IVD cells, as shown through mRNA expression and ECM biosynthesis 117,151,158,161,162,173,175,176 , but the degree of response seems to depend largely on cell type. This is also true for chondrogen- Indeed, increasing evidence suggests that interactive effects of tensile stretch and inflammatory signaling in AF cells 109,185,186 . This may be mediated by altered cytoskeletal mechanotransduction.…”

Section: Substrate Stiffness Effectsmentioning

confidence: 87%

Mechanotransduction and cell biomechanics of the intervertebral disc

et al. 2018

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Mechanical loading of the intervertebral disc (IVD) initiates cell-mediated remodeling events that contribute to disc degeneration. Cells of the IVD, nucleus pulposus (NP) and anulus fibrosus (AF), will exhibit various responses to different mechanical stimuli which appear to be highly dependent on loading type, magnitude, duration, and anatomic zone of cell origin. Cells of the NP, the innermost region of the disc, exhibit an anabolic response to low-moderate magnitudes of static compression, osmotic pressure, or hydrostatic pressure, while higher magnitudes promote a catabolic response marked by increased protease expression and activity. Cells of the outer AF are responsive to physical forces in a manner that depends on frequency and magnitude, as are cells of the NP, though they experience different forces, deformations, pressure, and osmotic pressure in vivo. Much remains to be understood of the mechanotransduction pathways that regulate IVD cell responses to loading, including responses to specific stimuli and also differences among cell types. There is evidence that cytoskeletal remodeling and receptor-mediated signaling are important mechanotransduction events that can regulate downstream effects like gene expression and posttranslational biosynthesis, all of which may influence phenotype and bioactivity. These and other mechanotransduction events will be regulated by known and to-be-discovered cell-matrix and cell-cell interactions, and depend on composition of extracellular matrix ligands for cell interaction, matrix stiffness, and the phenotype of the cells themselves. Here, we present a review of the current knowledge of the role of mechanical stimuli and the impact upon the cellular response to loading and changes that occur with aging and degeneration of the IVD.

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Section: Substrate Stiffness Effectsmentioning

confidence: 87%

Mechanotransduction and cell biomechanics of the intervertebral disc

et al. 2018

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“…Downstream targets of NF-κB signaling in IVD cells include many matrix-degrading enzymes [e.g., ADAMTS4 , ADAMTS5 , MMP1 , MMP2 , MMP3 , MMP9 , and MMP13 ( 25 )]. Blocking NF-κB activity has been shown to decrease matrix-degrading enzyme genes (e.g., MMP3 ) ( 36 ). However, in rabbit annulus fibrosis cells, NF-κB inhibition did not rescue the loss of PG or collagen synthesis in response to mechanical loading alone or in combined mechanical and inflammatory stimulation.…”

Section: Discussionmentioning

confidence: 99%

Actomyosin contractility confers mechanoprotection against TNFα-induced disruption of the intervertebral disc

2020

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Inflammation triggers degradation of intervertebral disc extracellular matrix (ECM), a hallmark of disc degeneration that contributes to back pain. Mechanosensitive nucleus pulposus cells are responsible for ECM production, yet the impact of a proinflammatory microenvironment on cell mechanobiology is unknown. Using gain- and loss-of-function approaches, we show that tumor necrosis factor–α (TNFα)–induced inflammation alters cell morphology and biophysical properties (circularity, contractility, cell stiffness, and hydraulic permeability) in a mechanism dependent on actomyosin contractility in a three-dimensional (3D) culture. We found that RhoA activation rescued cells from TNFα-induced mechanobiological disruption. Using a novel explant-in-hydrogel culture system, we demonstrate that nuclear factor kappa-B nuclear translocation and transcription are mechanosensitive, and its downstream effects on ECM degradation are regulated by actomyosin contractility. Results define a scaling relationship between circularity, contractility, and hydraulic permeability that is conserved from healthy to inflammatory microenvironments and is indicative of cell mechanobiological control across scales in 3D.

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“…While physiological mechanostimulation is favorable and even necessary to maintain IVD homeostasis, hyperphysiological mechanical loading is a well known contributor to IVD degeneration [5]. Furthermore, mechanical overloading interacts with inflammation and catabolism to cause degenerative disc disease (DDD) [6][7][8][9]. DDD, characterized by IVD structural failure and nociception [6], is the main cause of discogenic back pain.…”

Section: Introductionmentioning

confidence: 99%

TRPV4 Inhibition and CRISPR-Cas9 Knockout Reduce Inflammation Induced by Hyperphysiological Stretching in Human Annulus Fibrosus Cells

Cambria

Arlt

Wandel

et al. 2020

Cells

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Mechanical loading and inflammation interact to cause degenerative disc disease and low back pain (LBP). However, the underlying mechanosensing and mechanotransductive pathways are poorly understood. This results in untargeted pharmacological treatments that do not take the mechanical aspect of LBP into account. We investigated the role of the mechanosensitive ion channel TRPV4 in stretch-induced inflammation in human annulus fibrosus (AF) cells. The cells were cyclically stretched to 20% hyperphysiological strain. TRPV4 was either inhibited with the selective TRPV4 antagonist GSK2193874 or knocked out (KO) via CRISPR-Cas9 gene editing. The gene expression, inflammatory mediator release and MAPK pathway activation were analyzed. Hyperphysiological cyclic stretching significantly increased the IL6, IL8, and COX2 mRNA, PGE2 release, and activated p38 MAPK. The TRPV4 pharmacological inhibition significantly attenuated these effects. TRPV4 KO further prevented the stretch-induced upregulation of IL8 mRNA and reduced IL6 and IL8 release, thus supporting the inhibition data. We provide novel evidence that TRPV4 transduces hyperphysiological mechanical signals into inflammatory responses in human AF cells, possibly via p38. Additionally, we show for the first time the successful gene editing of human AF cells via CRISPR-Cas9. The pharmacological inhibition or CRISPR-based targeting of TRPV4 may constitute a potential therapeutic strategy to tackle discogenic LBP in patients with AF injury.

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NF-κB Signaling Pathway in Controlling Intervertebral Disk Cell Response to Inflammatory and Mechanical Stressors

Cited by 26 publications

References 35 publications

Mechanotransduction and cell biomechanics of the intervertebral disc

Mechanotransduction and cell biomechanics of the intervertebral disc

Actomyosin contractility confers mechanoprotection against TNFα-induced disruption of the intervertebral disc

TRPV4 Inhibition and CRISPR-Cas9 Knockout Reduce Inflammation Induced by Hyperphysiological Stretching in Human Annulus Fibrosus Cells

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