Reoxygenation enhances tumour necrosis factor alpha-induced degradation of the extracellular matrix produced by chondrogenic cells

Markway, Brandon D.; Cho, H.; Anderson, Devon E.; Holden, Paul; Ravi, V.; Little, C.; Johnstone, Brian

doi:10.22203/ecm.v031a27

Cited by 10 publications

(13 citation statements)

References 34 publications

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“…As previously reported, TNFα exposure during the chondrogenic differentiation phase reduces chondrogenesis of MSCs (Markway et al, 2016). Although the TNFα concentrations used during chondrogenic differentiation in this in vitro study are higher than the TNFα concentrations in post-traumatic and OA joints (4-24 pg/ml, Sward et al, 2012;Tsuchida et al, 2014;Imamura et al, 2015;Alonso et al, 2020), our data indicate that in vitro pre-treatment with 50 ng/ml TNFα can be beneficial for cartilage regeneration in an inflamed environment.…”

Section: Discussionsupporting

confidence: 69%

Enhanced Chondrogenic Capacity of Mesenchymal Stem Cells After TNFα Pre-treatment

Voskamp

Koevoet

Somoza

et al. 2020

Front. Bioeng. Biotechnol.

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Mesenchymal stem cells (MSCs) are promising cells to treat cartilage defects due to their chondrogenic differentiation potential. However, an inflammatory environment during differentiation, such as the presence of the cytokine TNFα, inhibits chondrogenesis and limits the clinical use of MSCs. On the other hand, it has been reported that exposure to TNFα during in vitro expansion can increase proliferation, migration, and the osteogenic capacity of MSCs and therefore can be beneficial for tissue regeneration. This indicates that the role of TNFα on MSCs may be dependent on the differentiation stage. To improve the chondrogenic capacity of MSCs in the presence of an inflamed environment, we aimed to determine the effect of TNFα on the chondrogenic differentiation capacity of MSCs. Here, we report that TNFα exposure during MSC expansion increased the chondrogenic differentiation capacity regardless of the presence of TNFα during chondrogenesis and that this effect of TNFα during expansion was reversed upon TNFα withdrawal. Interestingly, pre-treatment with another pro-inflammatory cytokine, IL-1β, did not increase the chondrogenic capacity of MSCs indicating that the pro-chondrogenic effect is specific for TNFα. Finally, we show that TNFα pre-treatment increased the levels of SOX11 and active β-catenin suggesting that these intracellular effectors may be useful targets to improve MSC-based cartilage repair. Overall, these results suggest that TNFα pre-treatment, by modulating SOX11 levels and WNT/β-catenin signaling, could be used as a strategy to improve MSC-based cartilage repair.

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Section: Discussionsupporting

confidence: 69%

Enhanced Chondrogenic Capacity of Mesenchymal Stem Cells After TNFα Pre-treatment

Voskamp

Koevoet

Somoza

et al. 2020

Front. Bioeng. Biotechnol.

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“…Inflammation leads to cartilage degradation; therefore, inhibiting chondrocyte inflammation may be an efficient method for the treatment of OA. Previous studies have reported that TNF-α is a potent proinflammatory cytokine that induces apoptosis of chondrocytes, which had been enzymatically dissociated from OA knee cartilage ( 31 , 32 ). In order to study the effects of EAS treatment on TNF-α-mediated chondrocyte inflammation, a chondrocyte culture was established in vitro via stepwise 0.2% collagenase type II digestion; subsequently, the chondrocytes were treated with 10 µg/l TNF-α for various durations.…”

Section: Discussionmentioning

confidence: 99%

Electroacupuncture serum inhibits TNF-α-mediated chondrocyte inflammation via the Ras-Raf-MEK1/2-ERK1/2 signaling pathway

Chen¹,

Shao²,

Li³

et al. 2017

Molecular Medicine Reports

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The Ras-Raf-mitogen-activated protein kinase kinase (MEK)1/2-extracellular signal-regulated kinase (ERK)1/2 signaling pathway contributes to the release of chondral matrix-degrading enzymes and accelerates the degradation of articular cartilage. Electroacupuncture (EA) treatment has been widely used for the treatment of osteoarthritis (OA); however, the mechanism underlying the effects of EA on OA remains unclear. Therefore, the present study evaluated the anti-inflammatory effects and potential underlying mechanisms of EA serum (EAS) on tumor necrosis factor (TNF)-α-mediated chondrocyte inflammation. A total of 30 Sprague Dawley rats were randomly divided into three groups: The blank group; experimental group I, which received 15 min of EA treatment; and experimental group II, which received 30 min of EA treatment. Subsequently, serum samples were obtained. Chondrocytes were isolated from the knee cartilage of Sprague Dawley rats, and were identified using collagen type II immunohistochemistry. TNF-α-treated chondrocytes were used as a cell model, and subsequently the cells were treated with EAS from each group for various durations. The results demonstrated that EAS treatment significantly promoted the viability and inhibited the apoptosis of TNF-α-treated chondrocytes. In addition, interleukin (IL)-1β concentration was significantly increased in the model group compared with in the control group, whereas EAS significantly reduced IL-1β concentration in TNF-α-treated chondrocytes. Furthermore, the protein expression levels of Ras, Raf and MEK1/2 were reduced in the EAS groups compared with in the model group. EAS also significantly inhibited the phosphorylation of ERK1/2, and the expression of downstream regulators matrix metalloproteinase (MMP)-3 and MMP-13. In conclusion, these results indicated that EAS may inhibit TNF-α-mediated chondrocyte inflammation via the Ras-Raf-MEK1/2-ERK1/2 signaling pathway in vitro, thus suggesting that EAS may be considered a potential therapeutic strategy for the treatment of OA.

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“…The differences observed in the present study are due to the type of model system used, e.g. cell type, 2D vs 3D model, primary vs passage cells, free-swelling culture vs mechanical loading, uninterrupted oxygen tension using the biospherix system vs oxygen controlled incubators [47, 48]. Conversely in porcine cartilage explants, mechanical loading enhanced NO production at 5 and 20 % oxygen tension and the response was reduced at 1 % oxygen tension [11, 44].…”

Section: Discussionmentioning

confidence: 99%

Oxygen tension modulates the effects of TNFα in compressed chondrocytes

et al. 2016

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Objective and designOxygen tension and biomechanical signals are factors that regulate inflammatory mechanisms in chondrocytes. We examined whether low oxygen tension influenced the cells response to TNFα and dynamic compression.Materials and methodsChondrocyte/agarose constructs were treated with varying concentrations of TNFα (0.1–100 ng/ml) and cultured at 5 and 21 % oxygen tension for 48 h. In separate experiments, constructs were subjected to dynamic compression (15 %) and treated with TNFα (10 ng/ml) and/or L-NIO (1 mM) at 5 and 21 % oxygen tension using an ex vivo bioreactor for 48 h. Markers for catabolic activity (NO, PGE2) and tissue remodelling (GAG, MMPs) were quantified by biochemical assay. ADAMTS-5 and MMP-13 expression were examined by real-time qPCR. 2-way ANOVA and a post hoc Bonferroni-corrected t test were used to analyse data.ResultsTNFα dose-dependently increased NO, PGE2 and MMP activity (all p < 0.001) and induced MMP-13 (p < 0.05) and ADAMTS-5 gene expression (pp < 0.01) with values greater at 5 % oxygen tension than 21 %. The induction of catabolic mediators by TNFα was reduced by dynamic compression and/or L-NIO (all p < 0.001), with a greater inhibition observed at 5% than 21 %. The stimulation of GAG synthesis by dynamic compression was greater at 21 % than 5 % oxygen tension and this response was reduced with TNFα or reversed with L-NIO.ConclusionsThe present findings revealed that TNFα increased production of NO, PGE2 and MMP activity at 5 % oxygen tension. The effects induced by TNFα were reduced by dynamic compression and/or the NOS inhibitor, linking both types of stimuli to reparative activities. Future therapeutics should develop oxygen-sensitive antagonists which are directed to interfering with the TNFα-induced pathways.

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Reoxygenation enhances tumour necrosis factor alpha-induced degradation of the extracellular matrix produced by chondrogenic cells

Cited by 10 publications

References 34 publications

Enhanced Chondrogenic Capacity of Mesenchymal Stem Cells After TNFα Pre-treatment

Enhanced Chondrogenic Capacity of Mesenchymal Stem Cells After TNFα Pre-treatment

Electroacupuncture serum inhibits TNF-α-mediated chondrocyte inflammation via the Ras-Raf-MEK1/2-ERK1/2 signaling pathway

Oxygen tension modulates the effects of TNFα in compressed chondrocytes

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