TLR4, RAGE, and p‐JNK/JNK mediated inflammatory aggression in osteoathritic human chondrocytes are counteracted by redox‐sensitive phenolic olive compounds: Comparison with ibuprofen

Abstract

Osteoarthritic chondrocytes show an over‐activity of inflammatory catabolic mediators, and olive products have attracted attention because they were discovered to have some benefits on osteoarthritis patients. We investigated the mechanisms of action of olive leaf polyphenolic compounds in osteoarthritic chondrocytes (OACs) using a standardized leaf extract, ZeyEX, and its main phenolic component, oleuropein, also compared with anti‐inflammatory drug ibuprofen. OACs, isolated from joint‐cartilages of Grade 4 OA patients, were found to express COMP and MMP‐9 throughout their culture period. ZeyEX, oleuropein, and ibuprofen increased cell viability at concentrations of 1–100 nM, did not change at 500 nM–50 μM, but inhibited at ≥100 μM. The adherence profile of OACs increased with 1 μM of ibuprofen or ZeyEX and 10 nM–1 μM oleuropein. Although the markers for oxidative and nitrosative stresses (ROS and 3‐NT) generally inhibited by three agents, the inhibitory effect of ZeyEX on 3‐NT emerged dramatically (1 nM–10 μM). Lipid‐hydroperoxides and HNE‐adducts were also inhibited by each agent, but AGE‐adducts unchanged by oleuropein while reduced by ZeyEX and ibuprofen. Inflammatory biomarkers, IL‐1β, IL‐6, Casp‐1/ICE, and TNF‐α, were inhibited by three agents, however osteopontin and GM‐CSF by only ZeyEX and ibuprofen. A decreased COMP, TLR4, and RAGE expression levels were observed by three agents, but only the effects of ZeyEX was concentration‐dependent. In particular, ZeyEX and oleuropein improved COL2, inhibited p‐JNK/JNK, and increased GPx. COX2 was only inhibited by ibuprofen. The results indicate that polyphenolic‐olive compounds counteract redox‐sensitive inflammatory aggressions in osteoarthritic chondrocytes that may stop the progression of pathology and allow regeneration.

Effects of type II collagen hydrolysates on osteoarthritis through the NF-κB, Wnt/β-catenin and MAPK pathways

“…Therefore, it is speculated that BIIP can reduce OA by downregulating the p-JNK protein expression in a dose-dependent manner, consistent with the results of Elmazoglu. 50…”

Repurposing Inhaled Ibuprofenate, a Non Steroidal Anti‐Inflammatory Drug, as a Potential Adjuvant Treatment for Pneumonia, CARDS and its Aetiological Agent SARS‐CoV‐2

“…NaIHS would negatively modulate: IL-1β, 13 IL-4, 27 IL-6, 13 IL-8, 27 IL-10, 27 IL-18, 24 tumour necrosis factor-alpha (TNFα), 13 interferon-gamma (IFN-γ), 13 transforming growth factor-beta 1 (TGF-β1), 13 intercellular adhesion molecule-1 (ICAM-1), 13 vascular adhesion molecule-1 (VCAM-1), 28 Eselectin, 12 monocyte chemoattractant protein 1 (MCP-1), 27 chemokine (C-C motif) ligand 2 (CCL2), 27 growth factors granulocyte-macrophage colony-stimulating factor 29 and hepatocyte growth factor (HGF). 27 Through its effect on the above possible negative modulation of pro-inflammatory cytokines responsible for the processes of adhesion, migration, neutrophil NOD-like receptor protein 3 (NLRP3) inflammasome inhibition 22 : by cyclooxygenase 2 (COX2) inhibition effect, it might inhibit NLRP3 inflammasome activation, 24 which significantly reduces the levels of caspase-1, 24 interleukin-1β (IL-1β), 24 IL-18 24 and gasdermin-D (GSDMD) 24 ; NaIHS might inhibit NLRP3 inflammasome activation due to its agonist peroxisome proliferator-activated receptor-gamma (PPAR-γ) effect 21,23 and it might also inhibit NLRP3 inflammasome via inhibition of membrane volume anion chloride channel 23,25 ;…”

“…IL‐8, 27 IL‐10, 27 IL‐18, 24 tumor necrosis factor‐alpha (TNF‐α), 13 interferon‐gamma (IFN‐γ), 13 transforming growth factor‐beta 1 (TGF‐β1), 13 intercellular adhesion molecule‐1 (ICAM‐1), 13 vascular adhesion molecule‐1 (VCAM‐1), 28 E‐selectin, 12 monocyte chemoattractant protein 1 (MCP‐1), 27 chemokine (C‐C motif) ligand 2 (CCL2), 27 growth factors granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) 29 and hepatocyte growth factor (HGF) 27 ; (3) Down‐regulation of nitric oxide (NO) hyperproduction : see Table 3; (4) Inhibition of the main local inflammatory mediators : by COX2 inhibition effect, it may inhibit prostaglandins, 12 prostacyclins, 12 histamine, 38 bradykinins 6,33,39 and NO 31 and (5) Antiangiogenic effect : by COX‐2 inhibition effect, it would negatively modulate vascular endothelial growth factor (VEGF), 40,42 basic fibroblast growth factor (bFGF), 40,42 CCL2, 27 HGF, 27 extracellular signal‐regulated kinase 2 (ERK2), 40 mitogen‐activated protein kinase (MAPK), 40 cyclin‐dependent kinase 1/2 (CDK 1/2), 40 checkpoint kinase 1 (CHK1), 40 cyclin A, 40 via Apelin/G protein‐coupled receptor (APJ) 40 and, by COX‐independent effect, NaIHS would inhibit hypoxia inducible factor‐1 alpha (HIF‐1α) 37 and HIF‐2α 43 . .…”

“…NaIHS would negatively modulate: IL‐1β, 13 IL‐4, 27 IL‐6, 13 IL‐8, 27 IL‐10, 27 IL‐18, 24 tumour necrosis factor‐alpha (TNF‐α), 13 interferon‐gamma (IFN‐γ), 13 transforming growth factor‐beta 1 (TGF‐β1), 13 intercellular adhesion molecule‐1 (ICAM‐1), 13 vascular adhesion molecule‐1 (VCAM‐1), 28 E‐selectin, 12 monocyte chemoattractant protein 1 (MCP‐1), 27 chemokine (C‐C motif) ligand 2 (CCL2), 27 growth factors granulocyte‐macrophage colony‐stimulating factor 29 and hepatocyte growth factor (HGF) 27 …”

Dietary Interventions with Polyphenols in Osteoarthritis: A Systematic Review Directed from the Preclinical Data to Randomized Clinical Studies

“…Over the last few years, a number of polyphenols have been investigated regarding the mechanisms underlying their effects on OA ( Figure 1 ). It has been shown that HT can regulate sirtuin (SIRT)-6-mediated autophagy in chondrocytes [ 64 ] and oleuropein can suppress the NF-κB and MAPK signaling pathways [ 65 , 66 ]. Resveratrol is another polyphenol that promotes chondrocyte autophagy via regulation of the regulating AMPK/mTOR signaling pathway [ 67 ].…”