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.