Faculty of Medicine, Department of Medical Pharmacology, Cellular Stress Response & Signal Transduction Research Laboratory, Gazi University, Ankara, Turkey.
Faculty of Medicine, Department of Histology and Embryology, Kırsehir Ahi Evran University, Kırsehir, Turkey.
J Tissue Eng Regen Med. 2020 Dec;14(12):1841-1857. doi: 10.1002/term.3138. Epub 2020 Oct 5.
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.
骨关节炎软骨细胞表现出炎症分解代谢介质的过度活性，而橄榄油产品因其对骨关节炎患者具有一定益处而受到关注。我们使用标准化的叶提取物 ZeyEX 和其主要酚类成分橄榄苦苷研究了橄榄叶多酚化合物在骨关节炎软骨细胞 (OAC) 中的作用机制，并将其与抗炎药物布洛芬进行了比较。从 4 级 OA 患者的关节软骨中分离出的 OAC 在整个培养过程中均表达 COMP 和 MMP-9。ZeyEX、橄榄苦苷和布洛芬在 1-100 nM 浓度下增加细胞活力，在 500 nM-50 μM 浓度下不改变，但在≥100 μM 浓度下抑制细胞活力。OAC 的黏附谱随着 1 μM 布洛芬或 ZeyEX 和 10 nM-1 μM 橄榄苦苷的增加而增加。尽管三种药物通常抑制氧化和硝化应激标志物（ROS 和 3-NT），但 ZeyEX 对 3-NT 的抑制作用非常显著（1 nM-10 μM）。脂质过氧化物和 HNE 加合物也被三种药物抑制，但只有 ZeyEX 和布洛芬降低了 AGE 加合物，而橄榄苦苷则没有改变。三种药物均抑制炎性生物标志物 IL-1β、IL-6、Casp-1/ICE 和 TNF-α，但只有 ZeyEX 和布洛芬抑制骨桥蛋白和 GM-CSF。三种药物均降低了 COMP、TLR4 和 RAGE 的表达水平，但只有 ZeyEX 的作用呈浓度依赖性。特别是，ZeyEX 和橄榄苦苷增加了 COL2，抑制了 p-JNK/JNK，并增加了 GPx。只有布洛芬抑制 COX2。结果表明，多酚-橄榄化合物可对抗骨关节炎软骨细胞中氧化还原敏感的炎症侵袭，从而阻止病理进展并允许再生。
