Nuclear receptor 4A1 inhibits chondrocyte inflammation and cartilage degeneration in osteoarthritis by inhibiting NF-κB signal pathway.

IF 4.6 2区医学 Q2 IMMUNOLOGY

Inflammopharmacology Pub Date : 2025-02-18 DOI:10.1007/s10787-025-01646-9

Yawei Zhang, Hengheng Zheng, Baitong Li

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引用次数: 0

Abstract

Objective: The objective of this study is to explore the mechanism of nuclear receptor subfamily 4 group A member 1 (NR4A1) inhibiting the inflammatory response and cartilage degeneration of osteoarthritis (OA) chondrocytes by inhibiting the nuclear factor κB (NF-κB).

Methods: A total of 45 Sprague-Dawley (SD) rats were randomly divided into three groups (n = 15 in each group): the blank control group (BCG), OA model group (OAG), and NR4A1 overexpression group (OE-NR4A1). The rat model of knee OA was established by medial meniscectomy. A total of 1 week after the operation, the rat model of NR4A1 overexpression was established by injecting NR4A1 overexpression lentivirus into the articular cavity of rats; 5 weeks after the establishment of the model, the rats were killed, and the morphological changes of knee cartilage were observed by hematoxylin and eosin (HE) staining under light microscope. The expression of NR4A1 and NF-κB protein in cartilage tissue was detected by western blot, and the relative expression of NR4A1 and NF-κB mRNA in cartilage tissue was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The levels of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α in the supernatant of chondrocytes were detected by ELISA, and the apoptosis of chondrocytes was detected by TUNEL staining.

Results: The relative expression of NR4A1 mRNA and protein in knee cartilage of rats in OE-NR4A1 were raised compared with those of OAG and BCG (P < 0.05). The relative expression of NF-κB mRNA and protein expression in knee joint cartilage in OE-NR4A1 were reduced compared with those of OAG and BCG, while their expression in the OE-NR4A1 (200 μL) and OE-NR4A1 (300 μL) groups were lower than in the OE-NR4A1 (100 μL) group(P < 0.05). The knee cartilage Mankin's score and knee joint diameter in the OAG were raised compared with those in the BCG (P < 0.05), while those in the OE-NR4A1 were reduced compared with the OAG (P < 0.05), but higher than in the BCG; these measures in the OE-NR4A1 (200 μL) and OE-NR4A1 (300 μL) groups were lower than in the OE-NR4A1 (100 μL) group (P < 0.05). The levels of IL-6, TNF-α, and IL-1β in knee synovial fluid of rats in OE-NR4A1 were reduced compared with those in the OAG (P < 0.05), but raised compared with those in the BCG; and these in the OE-NR4A1 (200 μL) and OE-NR4A1 (300 μL) groups were lower than in the OE-NR4A1 (100 μL) group (P < 0.05). The scorch rate of chondrocytes in the OE-NR4A1 was reduced compared with that in the OAG and higher than that of the BCG, and this measure in the OE-NR4A1 (200 μL) and OE-NR4A1 (300 μL) groups was lower than in the OE-NR4A1 (100 μL) group (P < 0.05).

Conclusions: R4A1 can improve the level of intraarticular inflammatory factors by inhibiting the NF-κB signal pathway, thereby reducing intraarticular inflammation and cartilage degeneration, and it plays a protective role in OA.

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核受体4A1通过抑制NF-κB信号通路抑制骨关节炎软骨细胞炎症和软骨退变。

目的：本研究旨在探讨核受体亚家族4A组成员1 （NR4A1）通过抑制核因子κB （NF-κB）抑制骨关节炎（OA）软骨细胞炎症反应和软骨退变的机制。方法：将45只SD大鼠随机分为空白对照组（BCG）、OA模型组（OAG）和NR4A1过表达组（OE-NR4A1） 3组，每组15只。采用内侧半月板切除术建立大鼠膝关节炎模型。术后共1周，在大鼠关节腔内注射NR4A1过表达慢病毒，建立NR4A1过表达大鼠模型；造模5周后处死大鼠，光镜下苏木精、伊红（HE）染色观察膝关节软骨形态变化。采用western blot检测软骨组织中NR4A1和NF-κB蛋白的表达，采用实时定量反转录聚合酶链反应（qRT-PCR）检测软骨组织中NR4A1和NF-κB mRNA的相对表达量。ELISA法检测各组软骨细胞上清液中白细胞介素(IL)-6、IL-8、肿瘤坏死因子(TNF)-α水平，TUNEL染色法检测各组软骨细胞凋亡情况。结果：与OAG和BCG相比，OE-NR4A1组大鼠膝关节软骨中NR4A1 mRNA和蛋白的相对表达量升高(P)。结论：R4A1可通过抑制NF-κB信号通路改善关节内炎症因子水平，从而减轻关节内炎症和软骨退变，对骨性关节炎具有保护作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Inflammopharmacology IMMUNOLOGYTOXICOLOGY-TOXICOLOGY

CiteScore

8.00

自引率

3.40%

发文量

200

期刊介绍： Inflammopharmacology is the official publication of the Gastrointestinal Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Hungarian Experimental and Clinical Pharmacology Society (HECPS). Inflammopharmacology publishes papers on all aspects of inflammation and its pharmacological control emphasizing comparisons of (a) different inflammatory states, and (b) the actions, therapeutic efficacy and safety of drugs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e.g. ulcerative colitis, Crohn''s disease), parasitic diseases, toxicological manifestations of the effects of drugs and environmental agents, arthritic conditions, and inflammatory effects of injury or aging on skeletal muscle. The journal has seven main interest areas: -Drug-Disease Interactions - Conditional Pharmacology - i.e. where the condition (disease or stress state) influences the therapeutic response and side (adverse) effects from anti-inflammatory drugs. Mechanisms of drug-disease and drug disease interactions and the role of different stress states -Rheumatology - particular emphasis on methods of measurement of clinical response effects of new agents, adverse effects from anti-rheumatic drugs -Gastroenterology - with particular emphasis on animal and human models, mechanisms of mucosal inflammation and ulceration and effects of novel and established anti-ulcer, anti-inflammatory agents, or antiparasitic agents -Neuro-Inflammation and Pain - model systems, pharmacology of new analgesic agents and mechanisms of neuro-inflammation and pain -Novel drugs, natural products and nutraceuticals - and their effects on inflammatory processes, especially where there are indications of novel modes action compared with conventional drugs e.g. NSAIDs -Muscle-immune interactions during inflammation [...]