大黄素对膝骨关节炎大鼠软骨细胞铁死亡的影响及机制研究

doi:10.11958/20221976

天津医药 ›› 2023, Vol. 51 ›› Issue (10): 1090-1097.doi: 10.11958/20221976

大黄素对膝骨关节炎大鼠软骨细胞铁死亡的影响及机制研究

王柯¹(), 叶寒露²^,^△()

1.武汉市中医医院骨伤科（邮编430014）
2.内分泌科

收稿日期:2022-12-02 修回日期:2023-02-17 出版日期:2023-10-15 发布日期:2023-10-18
通讯作者: ^∆E-mail：jueax516@163.com
作者简介:王柯（1981），男，主治医师，主要从事膝关节骨性关节炎临床研究。E-mail：emf3q7@sina.com
基金资助:
武汉市中医药科研项目(wz22c62)

Effect and its mechanism of emodin on the ferroptosis of chondrocytes in rats with knee osteoarthritis

WANG Ke¹(), YE Hanlu²^,^△()

2. Department of Orthopedics and Traumatology
2. Department of Endocrinology, Wuhan Hospital of Traditional Chinese Medicine, Wuhan 430014, China

Received:2022-12-02 Revised:2023-02-17 Published:2023-10-15 Online:2023-10-18
Contact: ^∆E-mail：jueax516@163.com

王柯, 叶寒露. 大黄素对膝骨关节炎大鼠软骨细胞铁死亡的影响及机制研究[J]. 天津医药, 2023, 51(10): 1090-1097.

WANG Ke, YE Hanlu. Effect and its mechanism of emodin on the ferroptosis of chondrocytes in rats with knee osteoarthritis[J]. Tianjin Medical Journal, 2023, 51(10): 1090-1097.

摘要/Abstract

摘要：

目的探讨大黄素对膝骨关节炎（KOA）大鼠软骨细胞铁死亡的影响及其机制。方法 96只SD大鼠分为假手术（Sham）组、KOA组、大黄素（EMO）组、大黄素+Nrf2抑制剂（EMO+ML385）组，每组24只，除Sham组外，其余组均采用改良Hulth法构建KOA模型。酶联免疫吸附试验（ELISA）检测血清肿瘤坏死因子-α（TNF-α）、一氧化氮（NO）、前列腺素E2（PGE2）水平；肉眼观察膝关节大体形态；番红O-固绿染色观察膝关节软骨组织病理形态学；原位末端标记（TUNEL）染色检测膝关节软骨细胞凋亡率；生化试剂盒检测膝关节软骨组织中丙二醛（MDA）、活性氧（ROS）、谷胱甘肽（GSH）、亚铁离子（Fe²⁺）水平；实时荧光定量PCR（qRT-PCR）、蛋白免疫印迹或免疫组化检测膝关节软骨组织中基质金属蛋白酶（MMP）-3、MMP-13、Ⅱ型胶原α1（COL2A1）、前列腺素内过氧化物合酶2（PTGS2）、谷胱甘肽过氧化物酶4（GPX4）、长链脂酰辅酶A合成酶4（ACSL4）、核因子E2相关因子2（Nrf2）、血红素加氧酶-1（HO-1）mRNA或蛋白表达。结果与Sham组比较，KOA组大鼠血清TNF-α、NO、PGE2水平，膝关节软骨组织国际骨关节炎研究协会（OARSI）评分，细胞凋亡率，MMP-3、MMP-13、PTGS2 mRNA和蛋白表达，MDA、ROS、Fe²⁺水平，ACSL4阳性细胞比例和ACSL4、胞核Nrf2、HO-1蛋白表达升高，GSH水平、COL2A1 mRNA和蛋白表达、GPX4阳性细胞比例和GPX4、胞质Nrf2蛋白表达降低（P<0.05），关节软骨明显破坏。EMO可改善KOA大鼠炎症反应、膝关节软骨组织损伤和软骨细胞铁死亡，同时进一步激活Nrf2/HO-1信号通路，而ML385不仅抑制Nrf2/HO-1信号通路激活，还可减弱EMO对KOA大鼠膝关节软骨组织损伤和软骨细胞铁死亡的改善作用。结论大黄素可激活Nrf2/HO-1信号通路，抑制KOA大鼠软骨细胞铁死亡，保护膝关节软骨。

关键词: 大黄素, 骨关节炎, 膝, 关节炎, 实验性, 软骨细胞, 铁死亡, Nrf2/HO-1信号通路

Abstract:

Objective To investigate the effect and its mechanism of emodin on the ferroptosis of chondrocytes in rats with knee osteoarthritis (KOA). Methods A total of 96 SD rats were divided into the sham operation (sham) group, the KOA group, the emodin (EMO) group and the emodin+Nrf2 inhibitor (EMO+ML385) group, with 24 rats in each group. Except for the sham group, KOA rat models were established by modified Hulth method in each group. The tumor necrosis factor-α (TNF-α), nitric oxide (NO) and prostaglandin E2 (PGE2) levels were detected by enzyme-linked immunosorbent assay (ELISA). General morphology of knee joint was observed with naked eyes. The pathological morphology of knee joint cartilage was observed with safranine O-solid green staining. Apoptosis rate of chondrocytes of knee joint was detected by TdT-mediated dUTP nick end labeling (TUNEL) staining. Malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH) and ferrous ion (Fe²⁺) levels in knee joint cartilage were detected by biochemical reagent kit. Expression levels of matrix metalloproteinase (MMP)-3, MMP-13, collagen type II α1 (COL2A1), prostaglandin-endoperoxide synthase 2 (PTGS2), glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long chain family member 4 (ACSL4), nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA or protein in knee joint cartilage were detected by real-time fluorescence quantitative PCR (qRT-PCR), Western blot assay or immunohistochemistry. Results Compared with the sham group, the serum TNF-α, NO and PGE2 levels, Osteoarthritis Research Society International (OARSI) score, apoptosis rate, mRNA expression of MMP-3, MMP-13 and PTGS2, MDA, ROS, and Fe²⁺ levels, proportion of ACSL4 positive cells, and protein expression of ACSL4, nuclear Nrf2 and HO-1 increased in the KOA group. GSH levels, mRNA expression of COL2A1, proportion of GPX4 positive cells, and protein expression of GPX4 and cytoplasmic Nrf2 decreased (P<0.05). The articular cartilage was obviously damaged. EMO can improve the inflammatory reaction, knee joint cartilage tissue injury and chondrocyte ferroptosis of KOA rats, and further activate Nrf2/HO-1 signal pathway. ML385 not only inhibited the activation of Nrf2/HO-1 signal pathway, but also attenuated the improvement of EMO on knee joint cartilage tissue injury and chondrocyte ferroptosis of KOA rats. Conclusion Emodin can activate Nrf2/HO-1 signal pathway, inhibit chondrocyte ferroptosis and protect knee articular cartilage of KOA rats.

Key words: emodin, osteoarthritis, knee, arthritis, experimental, chondrocytes, ferroptosis, Nrf2/HO-1 signal pathway

中图分类号:

R684.3，R285.5

图/表 14

表1 引物序列

Tab.1 Primer sequence

基因名称	引物序列
MMP-3	上游：5′-TTTGGCCGTCTCTTCCATCC-3′
	下游：5′-GCATCGATCTTCTGGACGGT-3′
MMP-13	上游：5′-TTCTGGTCTTCTGGCACACG-3′
	下游：5′-TGGAGCTGCTTGTCCAGGT-3′
COL2A1	上游：5′-GGTAAGTGGGGCAAGACTGTTA-3′
	下游：5′-TGTTGTTTCTGGGTTCAGGTTT-3′
PTGS2	上游：5′-ATGTTCGCATTCTTTGCCCAG-3′
	下游：5′-TACACCTCTCCACCGATGAC-3′
GAPDH	上游：5′-ATGACAACTCCCTCAAGAT-3′
	下游：5′-GATCCACAACGGATACATT-3′

表2 各组大鼠血清TNF-α、NO、PGE2水平比较 (n=8,$\bar{x}±s$)

Tab.2 Comparison of serum TNF-α, NO and PGE2 levels between the four groups of rats

组别	TNF-α/（ng/L）	NO/（μg/L）	PGE2/（μg/L）
Sham组	48.97±6.38	30.64±4.19	0.23±0.06
KOA组	117.54±8.67^a	58.27±5.63^a	0.52±0.08^a
EMO组	69.85±7.52^b	37.52±4.56^b	0.31±0.06^b
EMO+ML385组	102.71±8.35^c	51.38±5.32^c	0.46±0.07^c
F	127.745^＊＊	51.816^＊＊	30.789^＊＊

图1 各组大鼠膝关节大体形态

Fig.1 General morphology of knee joint of rats in each group

图2 各组大鼠膝关节软骨组织病理形态学变化（番红O- 固绿染色，×200）

Fig.2 Pathological changes of knee joint cartilage tissue of rats in each group (safranine O-solid green staining, ×200)

表3 各组大鼠膝关节软骨OARSI评分和软骨细胞凋亡率比较 (n=8,$\bar{x}±s$)

Tab.3 Comparison of OARSI score of knee joint cartilage and apoptosis rate of chondrocytes between the four groups of rats

组别	OARSI评分/分	凋亡率/%
Sham组	1.46±0.31	4.34±0.62
KOA组	6.50±0.69^a	21.17±3.74^a
EMO组	3.64±0.45^b	8.26±1.45^b
EMO+ML385组	5.78±0.52^c	17.58±2.67^c
F	158.438^＊＊	83.641^＊＊

图3 各组大鼠膝关节软骨细胞凋亡情况（TUNEL染色，×200）

Fig.3 Apoptosis of chondrocytes of knee joint of rats in each group (TUNEL staining, ×200)

表4 各组大鼠膝关节软骨组织中MMP-3、MMP-13、COL2A1、PTGS2 mRNA相对表达水平比较 (n=8,$\bar{x}±s$)

Tab.4 Comparison of MMP-3, MMP-13, COL2A1 and PTGS2 mRNA relative expression levels in knee joint cartilage between the four groups of rats

组别	MMP-3	MMP-13	COL2A1	PTGS2
Sham组	0.98±0.09	1.01±0.10	1.00±0.08	1.02±0.09
KOA组	3.52±0.13^a	2.73±0.11^a	0.39±0.06^a	3.68±0.12^a
EMO组	2.16±0.10^b	1.85±0.12^b	0.75±0.08^b	1.54±0.08^b
EMO+ML385组	3.04±0.12^c	2.30±0.13^c	0.48±0.07^c	3.07±0.11^c
F	806.586^＊＊	324.090^＊＊	114.629^＊＊	1 225.437^＊＊

表5 各组大鼠膝关节软骨组织中MDA、ROS、GSH、Fe2+水平比较 (n=8,$\bar{x}±s$)

Tab.5 Comparison of MDA, ROS, GSH and Fe2+ levels in knee joint cartilage of rats between the four groups

组别	MDA/（μmol/g）	ROS	GSH/（μmol/g）	Fe²⁺/（mg/g）
Sham组	3.41±0.48	1.00±0.00	7.98±0.75	0.26±0.06
KOA组	8.96±0.65^a	3.68±0.37^a	3.61±0.49^a	0.64±0.08^a
EMO组	5.37±0.54^b	1.95±0.26^b	6.37±0.64^b	0.41±0.07^b
EMO+ ML385组	8.02±0.66^c	3.07±0.31^c	4.29±0.56^c	0.58±0.06^c
F	148.183^＊＊	150.714^＊＊	83.386^＊＊	51.128^＊＊

表6 各组大鼠膝关节软骨组织中GPX4、ACSL4阳性细胞比例比较 (n=8,%,$\bar{x}±s$)

Tab.6 Comparison of the proportion of GPX4 and ACSL4 positive cells in knee joint cartilage between the four groups of rats

组别	GPX4	ACSL4
Sham组	83.21±7.54	28.64±6.38
KOA组	42.16±6.89^a	69.31±8.14^a
EMO组	71.39±8.43^b	40.52±7.03^b
EMO+ML385组	50.98±7.85^c	58.26±7.69^c
F	47.394^＊＊	48.728^＊＊

图4 各组大鼠膝关节软骨组织中GPX4、ACSL4阳性表达情况（免疫组化染色，×200）

Fig.4 Positive expression of GPX4 and ACSL4 in knee joint cartilage of rats in each group (immunohistochemistry staining, ×200)

图5 各组大鼠膝关节软骨组织中MMP-3、MMP-13、COL2A1、PTGS2蛋白表达

Fig.5 Protein expression of MMP-3, MMP-13, COL2A1 and PTGS2 in knee joint cartilage of rats in each group

表7 各组大鼠膝关节软骨组织中MMP-3、MMP-13、COL2A1、PTGS2蛋白相对表达水平比较 (n=8,$\bar{x}±s$)

Tab.7 Comparison of the protein relative expression levels of MMP-3, MMP-13, COL2A1 and PTGS2 in knee joint cartilage between the four groups of rats

组别	MMP-3	MMP-13	COL2A1	PTGS2
Sham组	0.23±0.04	0.29±0.05	0.79±0.05	0.19±0.04
KOA组	0.85±0.06^a	0.93±0.06^a	0.38±0.04^a	0.72±0.05^a
EMO组	0.34±0.05^b	0.42±0.05^b	0.71±0.05^b	0.28±0.04^b
EMO+ML385组	0.72±0.06^c	0.84±0.06^c	0.46±0.04^c	0.53±0.06^c
F	249.676^＊＊	256.525^＊＊	149.984^＊＊	199.799^＊＊

图6 各组大鼠膝关节软骨组织中GPX4、ACSL4、Nrf2、HO-1蛋白表达

Fig.6 Protein expression of GPX4, ACSL4, Nrf2 and HO-1 in knee joint cartilage of rats in each group

表8 各组大鼠膝关节软骨组织中GPX4、ACSL4、Nrf2、HO-1蛋白相对表达水平比较 (n=8,$\bar{x}±s$)

Tab.8 Comparison of the protein relative expression levels of GPX4, ACSL4, Nrf2 and HO-1 in knee joint cartilage of rats between the four groups

组别	GPX4	ACSL4	HO-1	胞质Nrf2	胞核Nrf2
Sham组	0.82±0.05	0.12±0.03	0.46±0.04	0.89±0.05	0.17±0.03
KOA组	0.36±0.04^a	0.39±0.05^a	0.58±0.05^a	0.74±0.07^a	0.29±0.05^a
EMO组	0.72±0.06^b	0.20±0.04^b	1.13±0.06^b	0.23±0.05^b	0.94±0.06^b
EMO+ML385组	0.43±0.05^c	0.31±0.05^c	0.71±0.05^c	0.56±0.06^c	0.49±0.05^c
F	154.850^＊＊	60.444^＊＊	267.085^＊＊	191.289^＊＊	385.881^＊＊

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大黄素对膝骨关节炎大鼠软骨细胞铁死亡的影响及机制研究

Effect and its mechanism of emodin on the ferroptosis of chondrocytes in rats with knee osteoarthritis

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