NF-κB Signaling Pathways in Osteoarthritic Cartilage Destruction

Choi, Moon‐Chang; Jo, Jiwon; Park, Jonggwan; Kang, Hee Kyoung; Park, Yoonkyung

doi:10.3390/cells8070734

Cited by 366 publications

(306 citation statements)

References 217 publications

(271 reference statements)

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“…Genes in these categories include NF-kB subunits, chemokine receptors, interleukins, MAP kinases, TNF ligands, and other cytokines. This is consistent with previous studies that have demonstrated that FN-f treatment stimulates a proinflammatory response via MAP kinases and NF-κB signaling 15,16,25,41,51 , as well as the established role of inflammation in the progression of OA 24,30,39,40,42,43,47,52,53 . Genes downregulated in response to FN-f were enriched for GO terms for development and morphogenesis and included HOX genes, TGFBR2, and COL8A2, among others.…”

Section: Fn-f Induces Transcription Of Proinflammatory Genes and Pathsupporting

confidence: 93%

“…To determine pathways that were affected by FN-f treatment, we identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were enriched in each of the four gene sets (Fig 4B). Early-response upregulated genes were enriched for TNF and NF-κB pathways, both of which have been implicated in OA and even targeted for therapeutic OA treatments 30,42,54 . Intriguingly, late-response upregulated genes were most strongly enriched for the ferroptosis pathway, a form of programmed cell death dependent on iron and accumulation of lipid peroxides induced by reactive oxygen species, which have been implicated in OA 55 .…”

Section: Fn-f Induces Transcription Of Proinflammatory Genes and Pathmentioning

confidence: 99%

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Transcriptional response of human articular chondrocytes treated with fibronectin fragments: anin vitromodel of the osteoarthritis phenotype

Reed¹,

Ulici²,

Kim³

et al. 2020

Preprint

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Objective: Fibronectin is a matrix protein that is fragmented during cartilage degradation in osteoarthritis (OA). Treatment of chondrocytes with fibronectin fragments (FN-f) has been used to model OA in vitro, but the system has not been fully characterized. This study sought to define the transcriptional response of chondrocytes to FN-f, and directly compare it to responses traditionally observed in OA.Design: Normal human femoral chondrocytes isolated from tissue donors were treated with either FN-f or PBS (control) for 3, 6, or 18 hours. RNA-seq libraries were compared between time-matched FN-f and control samples in order to identify changes in gene expression over time. Differentially expressed genes were compared to a published OA gene set and used for pathway, transcription factor motif, and kinome analysis.Results: FN-f treatment resulted in 1,224 differentially expressed genes over the time course. Genes that are up-or downregulated in OA were significantly up-(p < 0.00001) or downregulated (p < 0.0004) in response to FN-f. Early response genes were involved in proinflammatory pathways and their promoters were enriched for NF-κB-related motifs, whereas many late response genes were involved in ferroptosis, and their promoters were enriched for Jun-related motifs. Highly upregulated kinases included CAMK1G, IRAK2, and the uncharacterized kinase DYRK3, while growth factor receptors TGFBR2 and FGFR2 were downregulated.Conclusions: FN-f treatment of normal human articular chondrocytes recapitulated many key aspects of the OA chondrocyte phenotype. This in vitro model is promising for future OA studies, especially considering its compatibility with genomics and genome-editing techniques.

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Section: Fn-f Induces Transcription Of Proinflammatory Genes and Pathsupporting

confidence: 93%

Section: Fn-f Induces Transcription Of Proinflammatory Genes and Pathmentioning

confidence: 99%

Transcriptional response of human articular chondrocytes treated with fibronectin fragments: anin vitromodel of the osteoarthritis phenotype

Reed¹,

Ulici²,

Kim³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…This study revealed that NFκB induced catabolic gene expression through NFκB response elements, thereby promoting the expression of major pro-inflammatory and destructive mediators, including cyclooxygenase 2 (COX2), prostaglandin E2 (PGE2), and inducible nitric oxide synthase (iNOS). Particularly, the loss of iNOS appeared to attenuate the process of inflammation [12][13][14]. Interestingly, the data shown in Figure 1A above indicated that LPS-induced NO production in vitro was inhibited in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 85%

Inhibitory Effects of Myrtucommuacetalone 1 (MCA-1) from Myrtus Communis on Inflammatory Response in Mouse Macrophages

et al. 2019

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1) Introduction: Reactive oxygen species (ROS) and nitric oxide (NO) are key signaling molecules that play important roles in the progression of inflammatory disorders. The objective of this study was to explore the use of myrtucommuacetalone-1 (MCA-1), as a novel compound of natural origin and a potential anti-inflammatory agent.(2) Methodology: The anti-inflammatory potential of MCA-1, which was isolated from Myrthus communis Linn, was determined by assaying superoxide, hydrogen peroxide, and nitric oxide production in macrophages. Furthermore, the effects of the compound were analyzed via phosphorylation and translocation of the transcription factor NF kappa B, which is a key regulator of iNOS activation. The effect of MCA-1 on the inducible nitric oxide synthase (iNOS) enzyme was also examined using in silico docking studies. The anticancer potential for MCA-1 was evaluated with an MTT cytotoxic assay. (3) Results: In stimulated macrophages, MCA-1 inhibited superoxide production by 48%, hydrogen peroxide by 53%, and nitric oxide (NO) with an IC 50 of <1 µg/mL. MCA-1 also showed a very strong binding pattern within the active site of the inducible nitric oxide synthase enzyme. Furthermore, 25 µg/mL of MCA-1 inhibited inducible nitric oxide synthase expression and abolished transcription factor (NFκB) phosphorylation and translocation to the nucleus. Cytotoxicity analyses of MCA-1 on 3T3 mouse fibroblasts, CC1 liver cell line, J774.2, macrophages and MDBK bovine kidney epithelial cell, yielded IC 50 values of 6.53 ± 1.2, 4.6 ± 0.7, 5 ± 0.8, and 4.6 ± 0.7, µg/mL, respectively. (4) Conclusion: Our results suggest that MCA-1, a major phloroglucinol-type compound, shows strong anti-inflammatory activity and has a potential to be a leading therapeutic agent in the future.

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“…More importantly, inhibition of NF-κB has been shown to limit the production of proinflammatory cytokines like IL-6 and CXCL10 in mouse models resulting in reduced mortality [34]. Dysregulation of NF-κB activity has been broadly implicated in the production of inflammatory cytokines (TNFα, IL-1β, IL-6) and cell apoptosis [35][36][37]. Also, it has been reported that NF-κB signaling pathways can coordinate with other hallmark pro-inflammatory transcription factors in the immune response [38].…”

Section: Lmwf5a Down-regulates Pro-inflammatory Transcription Factorsmentioning

confidence: 99%

The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the “cytokine storm” in COVID-19 patients: a hypothesis

et al. 2020

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Background: A common complication of viral pulmonary infections, such as in the ongoing COVID-19 pandemic, is a phenomenon described as a "cytokine storm". While poorly defined, this hyperinflammatory response results in diffuse alveolar damage. The low molecular weight fraction of commercial human serum albumin (LMWF5A), a novel biologic in development for osteoarthritis, demonstrates beneficial in vitro immunomodulatory effects complimentary to addressing inflammation, thus, we hypothesize that LMWF5A could improve the clinical outcomes of COVID-19 by attenuating hyperinflammation and the potential development of a cytokine storm.Presentation of the hypothesis: A variety of human in vitro immune models indicate that LMWF5A reduces the production of pro-inflammatory cytokines implicated in cytokine storm associated with COVID-19. Furthermore, evidence suggests LMWF5A also promotes the production of mediators required for resolving inflammation and enhances the barrier function of endothelial cultures. Testing the hypothesis: A randomized controlled trial, to evaluate the safety and efficacy of nebulized LMWF5A in adults with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection, was developed and is currently under review by the Food and Drug Administration. Implications of hypothesis: If successful, this therapy may attenuate the cytokine storm observed in these patients and potentially reduce mortality, increase ventilation free days, improve oxygenation parameters and consequently lessen the burden on patients and the intensive care unit. Conclusions: In conclusion, in vitro findings suggest that the immunomodulatory effects of LMWF5A make it a viable candidate for treating cytokine storm and restoring homeostasis to the immune response in COVID-19.

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NF-κB Signaling Pathways in Osteoarthritic Cartilage Destruction

Cited by 366 publications

References 217 publications

Transcriptional response of human articular chondrocytes treated with fibronectin fragments: anin vitromodel of the osteoarthritis phenotype

Transcriptional response of human articular chondrocytes treated with fibronectin fragments: anin vitromodel of the osteoarthritis phenotype

Inhibitory Effects of Myrtucommuacetalone 1 (MCA-1) from Myrtus Communis on Inflammatory Response in Mouse Macrophages

The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the “cytokine storm” in COVID-19 patients: a hypothesis

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