Cells from Degenerative Intervertebral Discs Demonstrate Unfavorable Responses to Mechanical and Inflammatory Stimuli

Sowa, Gwendolyn; Coelho, João Paulo; Vo, Nam; Pacek, Corey A.; Westrick, Edward; Kang, James D.

doi:10.1097/phm.0b013e31825f145a

Cited by 21 publications

(26 citation statements)

References 22 publications

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“…AF cell strain is known to interact with pro-inflammatory cytokines, and the current results help explain the finding that AF cells obtained from a rabbit IVD degeneration model demonstrated enhanced pro-inflammatory responses to mechanical and inflammatory stimuli (Sowa et al, 2012). Specifically, AF cells in degenerated rabbit IVDs may have been chronically exposed to TNF-α resulting in heightened mechanosensitivity.…”

Section: Discussionsupporting

confidence: 69%

“…Annulus fibrosus (AF) defects and delamination induce strain ‘concentrations’, cell death, and pro-inflammatory cytokine production (Adams et al, 2015; Korecki et al, 2008; Michalek et al, 2010; Ulrich et al, 2007; Walter et al, 2011). In contrast, dynamic loading is considered healthy since it can enhance IVD matrix production; although this healthy response to load is altered with degeneration perhaps because dynamic compression facilitates transport of pro-inflammatory cytokines into healthy IVDs where they can persist and induce biomechanical changes (Sowa et al, 2012; Stokes and Iatridis, 2004; Wuertz et al, 2009; Walter et al, 2015a). …”

Section: Introductionmentioning

confidence: 99%

“…Physiological strains stimulated anti-catabolic effects on AF cells in vitro while pathological strains resulted in a detrimental responses (Gilbert et al, 2010; Sowa et al, 2011; Sowa et al, 2012; Gawri et al, 2014). Pathologically high mechanical strain on AF cells exposed to IL-1β induced greater catabolic gene expression compared to mechanical strain alone (Sowa et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Do mechanical strain and TNF-α interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells?

Likhitpanichkul

Torre

Gruen

et al. 2016

Journal of Biomechanics

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During intervertebral disc (IVD) injury and degeneration, annulus fibrosus (AF) cells experience large mechanical strains in a pro-inflammatory milieu. We hypothesized that TNF-α, an initiator of IVD inflammation, modifies AF cell mechanobiology via cytoskeletal changes, and interacts with mechanical strain to enhance pro-inflammatory cytokine production. Human AF cells (N=5, Thompson grades 2–4) were stretched uniaxially on collagen-I coated chambers to 0%, 5% (physiological) or 15% (pathologic) strains at 0.5 Hz for 24 hours under hypoxic conditions with or without TNF-α (10 ng/mL). AF cells were treated with anti-TNF-α and anti-IL-6. ELISA assessed IL-1β, IL-6, and IL-8 production and immunocytochemistry measured F-actin, vinculin and α-tubulin in AF cells. TNF-α significantly increased AF cell proinflammatory cytokine production compared to basal conditions (IL-1β:2.0±1.4 to 84.0±77.3, IL-6:10.6±9.9 to 280.9±214.1, IL-8:23.9±26.0 to 5125.1±4170.8 pg/ml for basal and TNF-α treatment, respectively) as expected, but mechanical strain did not. Pathologic strain in combination with TNF-α increased IL-1β, and IL-8 but not IL-6 production of AF cells. TNF-α treatment altered F-actin and α-tubulin in AF cells, suggestive of altered cytoskeletal stiffness. Anti-TNF-α (infliximab) significantly inhibited pro-inflammatory cytokine production while anti-IL-6 (atlizumab) did not. In conclusion, TNF-α altered AF cell mechanobiology with cytoskeletal remodeling that potentially sensitized AF cells to mechanical strain and increased TNF-α-induced pro-inflammatory cytokine production. Results suggest an interaction between TNF-α and mechanical strain and future mechanistic studies are required to validate these observations.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Do mechanical strain and TNF-α interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells?

Likhitpanichkul

Torre

Gruen

et al. 2016

Journal of Biomechanics

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“…Another reason can be elevated expression of TIMP1. It has been shown before that healthy disc cells respond to stress by upregulation of matrix metalloproteinase inhibitors (TIMPs) [66], which inhibit the activity of MMPs in a 1:1 stoichiometry. In particular, TIMP-1 forms a complex with the catalytic domain of MMP-3, reducing its activity in the NP tissue [54].…”

Section: Discussionmentioning

confidence: 99%

An Inflammatory Nucleus Pulposus Tissue Culture Model to Test Molecular Regenerative Therapies: Validation with Epigallocatechin 3-Gallate

Krupková

Hlavna

Tahmasseb

et al. 2016

IJMS

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Organ cultures are practical tools to investigate regenerative strategies for the intervertebral disc. However, most existing organ culture systems induce severe tissue degradation with only limited representation of the in vivo processes. The objective of this study was to develop a space- and cost-efficient tissue culture model, which represents degenerative processes of the nucleus pulposus (NP). Intact bovine NPs were cultured in a previously developed system using Dyneema jackets. Degenerative changes in the NP tissue were induced either by the direct injection of chondroitinase ABC (1–20 U/mL) or by the diffusion of interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) (both 100 ng/mL) from the culture media. Extracellular matrix composition (collagens, proteoglycans, water, and DNA) and the expression of inflammatory and catabolic genes were analyzed. The anti-inflammatory and anti-catabolic compound epigallocatechin 3-gallate (EGCG, 10 µM) was employed to assess the relevance of the degenerative NP model. Although a single injection of chondroitinase ABC reduced the proteoglycan content in the NPs, it did not activate cellular responses. On the other hand, IL-1β and TNF-α significantly increased the mRNA expression of inflammatory mediators IL-6, IL-8, inducible nitric oxide synthase (iNOS), prostaglandin-endoperoxide synthase 2 (PTGS2) and matrix metalloproteinases (MMP1, MMP3, and MMP13). The cytokine-induced gene expression in the NPs was ameliorated with EGCG. This study provides a proof of concept that inflammatory NP cultures, with appropriate containment, can be useful for the discovery and evaluation of molecular therapeutic strategies against early degenerative disc disease.

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“…Degenerative cells have a decreased ability to respond positively to beneficial levels of mechanical strain and demonstrate a disproportionate response to inflammatory stimuli. This may, in part, help explaining differential responses to motion-based therapies in patients with IVD degeneration (39). …”

Section: Discussionmentioning

confidence: 99%

Acid-sensing ion channels in healthy and degenerated human intervertebral disc

Cuesta¹,

Soto

García‐Suárez³

et al. 2014

Connective Tissue Research

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Acid-sensing ion channels (ASICs) are a family of H(+)-gated voltage-insensitive ion channels that respond to extracellular acidification by regulating transmembrane Ca(2+) flux. Moreover, ASICs can also be gated by mechanical forces and may function as mechanosensors. The cells of the intervertebral disc (IVD) have an unusual acidic and hyperosmotic microenvironment. Changes in the pH and osmolarity determine the viability of IVD cells and the composition of the extracellular matrix, and both are the basis of IVD degeneration. In this study, the expression of ASICs (ASIC1, ASIC2, ASIC3 and ASIC4) mRNAs and proteins in human healthy and degenerated IVD was evaluated by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot. The distribution of ASIC proteins was determined by immunohistochemistry. The mRNAs for all ASICs were detected in normal human IVD, and significantly increased levels were found in degenerated IVD. Western blots demonstrated the presence of proteins with estimated molecular weights of approximately 68-72 kDa. In both the annulus fibrosus (AF) and nucleus pulposus (NP) of normal IVD, ASIC2 is the most frequently expressed ASIC followed by ASIC3, ASIC1 and ASIC4. In the AF of degenerated IVD, there was a significant increase in the number of ASIC1 and ASIC4 positive cells, whereas in the NP, we found significant increase of expression of ASIC1, ASIC2 and ASIC3. These results describe the occurrence and localization of different ASICs in human healthy IVD, and their increased expression in degenerated IVD, thus suggesting that ASICs may be involved in IVD degeneration.

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Cells from Degenerative Intervertebral Discs Demonstrate Unfavorable Responses to Mechanical and Inflammatory Stimuli

Cited by 21 publications

References 22 publications

Do mechanical strain and TNF-α interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells?

Do mechanical strain and TNF-α interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells?

An Inflammatory Nucleus Pulposus Tissue Culture Model to Test Molecular Regenerative Therapies: Validation with Epigallocatechin 3-Gallate

Acid-sensing ion channels in healthy and degenerated human intervertebral disc

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