隐丹参酮调节HIF-1α/BNIP3信号通路对兔膝骨关节炎模型软骨细胞自噬和凋亡的影响

doi:10.11958/20230861

天津医药 ›› 2024, Vol. 52 ›› Issue (4): 372-378.doi: 10.11958/20230861

隐丹参酮调节HIF-1α/BNIP3信号通路对兔膝骨关节炎模型软骨细胞自噬和凋亡的影响

王柯¹(), 叶寒露²^,^△()

1 武汉市中医医院骨伤科（邮编430014）
2 武汉市中医医院内分泌科（邮编430014）

收稿日期:2023-06-16 修回日期:2023-08-04 出版日期:2024-04-15 发布日期:2024-04-19
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)

Impacts of cryptotanshinone on autophagy and apoptosis of chondrocytes in rabbit model of knee osteoarthritis by regulating HIF-1α/BNIP3 signaling pathway

WANG Ke¹(), YE Hanlu²^,^△()

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

Received:2023-06-16 Revised:2023-08-04 Published:2024-04-15 Online:2024-04-19
Contact: ^△E-mail：jueax516@163.com

王柯, 叶寒露. 隐丹参酮调节HIF-1α/BNIP3信号通路对兔膝骨关节炎模型软骨细胞自噬和凋亡的影响[J]. 天津医药, 2024, 52(4): 372-378.

WANG Ke, YE Hanlu. Impacts of cryptotanshinone on autophagy and apoptosis of chondrocytes in rabbit model of knee osteoarthritis by regulating HIF-1α/BNIP3 signaling pathway[J]. Tianjin Medical Journal, 2024, 52(4): 372-378.

摘要/Abstract

摘要：

目的探究隐丹参酮调节缺氧诱导因子-1α（HIF-1α）/腺病毒E1B19kDa相互作用蛋白3（BNIP3）信号通路对兔膝骨关节炎（KOA）模型软骨细胞自噬和凋亡的影响。方法取新西兰兔并以改良Videman法构建兔KOA模型，随机分为模型组、空载组、隐丹参酮组、HIF-1α敲低组、隐丹参酮+HIF-1α敲低组，每组9只；另取9只新西兰兔为对照组。分组干预后以Lequesne MG的膝关节级别评估法对兔膝关节临床症状（局部疼痛、步态、关节活动、关节肿胀）进行评分；HE染色检测兔膝关节软骨组织的退变情况并进行改良Mankin's评分；TUNEL染色检测兔膝关节软骨组织细胞凋亡情况；酶联免疫吸附试验（ELISA）检测兔血清炎性因子白细胞介素（IL）-6、IL-18、IL-10水平；蛋白免疫印迹实验检测兔膝关节软骨组织自噬（LC3、Beclin-1）、凋亡（Bax、Cleaved Caspase-3）和HIF-1α/BNIP3信号通路相关蛋白表达。结果与对照组比较，模型组兔膝关节软骨组织出现明显退变症状，局部疼痛、步态、关节活动及关节肿胀评分、改良Mankin's评分、凋亡率、血清IL-18及IL-6水平、软骨组织LC3Ⅱ/LC3Ⅰ、Beclin-1、Bax、Cleaved Caspase-3、BNIP3蛋白表达水平升高，血清IL-10水平、软骨组织HIF-1α蛋白表达水平降低（P<0.05）。与模型组比较，隐丹参酮组兔膝关节软骨组织退变症状减轻，局部疼痛、步态、关节活动及关节肿胀评分、改良Mankin's评分、凋亡率、血清IL-18及IL-6水平、软骨组织LC3Ⅱ/LC3Ⅰ、Beclin-1、Bax、Cleaved Caspase-3、BNIP3蛋白表达水平降低，血清IL-10水平、软骨组织HIF-1α蛋白表达水平升高（P<0.05）；HIF-1α敲低组兔膝关节软骨组织退变症状加重，局部疼痛、步态、关节活动及关节肿胀评分、改良Mankin's评分、凋亡率、血清IL-18及IL-6水平、软骨组织LC3Ⅱ/LC3Ⅰ、Beclin-1、Bax、Cleaved Caspase-3、BNIP3蛋白表达水平升高，血清IL-10水平、软骨组织HIF-1α蛋白表达水平降低（P<0.05）；空载组兔各指标无明显变化（P>0.05）。隐丹参酮+HIF-1α敲低组较隐丹参酮组兔膝关节软骨组织退变症状加重，局部疼痛、步态、关节活动及关节肿胀评分、改良Mankin's评分、凋亡率、血清IL-18及IL-6水平、软骨组织LC3Ⅱ/LC3Ⅰ、Beclin-1、Bax、Cleaved Caspase-3、BNIP3蛋白表达水平升高，血清IL-10水平、软骨组织HIF-1α蛋白表达水平降低（P<0.05）；较HIF-1α敲低组上述指标变化相反。结论隐丹参酮可通过上调HIF-1α、下调BNIP3表达，抑制炎症及自噬，减轻KOA兔膝关节软骨组织退变，改善其临床症状。

关键词: 隐丹参酮, 骨关节炎, 膝, 软骨细胞, 自噬, 凋亡, HIF-1α/BNIP3

Abstract:

Objective To investigate the impact of cryptotanshinone on autophagy and apoptosis of chondrocytes in a rabbit knee osteoarthritis (KOA) model by regulating the hypoxia inducible factor-1α (HIF-1α)/BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) signaling pathway. Methods New Zealand rabbits were selected to construct the rabbit KOA model using the improved Videman method. Rabbits were randomly divided into the model group, the empty group, the cryptotanshinone group, the HIF-1α knockdown group and the cryptotanshinone+HIF-1α knockdown group, with 9 rabbits in each group. Another 9 New Zealand rabbits were taken as the control group. After grouping and intervention, Lequesne MG knee joint level assessment method was used to score clinical symptoms of knee joints (local pain, gait, joint activity and joint swelling) of rabbits. HE staining was used to detect the cartilage degeneration of rabbit knee joint cartilage tissue, and modified Mankin's score was performed. TUNEL staining was used to detect the apoptosis of articular cartilage histiocytes of rabbits. Enzyme-linked immunosorbent assay (ELISA) method was used to detect serum levels of inflammatory cytokines interleukin-6 (IL-6), IL-18 and IL-10 in rabbits. Western blot experiment was used to detect the expression of autophagy (LC3, Beclin-1), apoptosis (Bax, Cleaved Caspase-3) and HIF-1α/BNIP3 signaling pathway related proteins in knee cartilage tissue of rabbits. Results Compared with the control group, the knee joint cartilage tissue of rabbits showed obvious degenerative symptoms, the scores of local pain, gait, joint activity and joint swelling, the modified Mankin's score, apoptosis rate, levels of serum IL-18 and IL-6, and the expression of LC3Ⅱ/LC3Ⅰ and Beclin-1, Bax, Cleaved Caspase-3, BNIP3 proteins in cartilage tissue were increased in the model group, and the serum level of IL-10 and the expression of HIF-1α protein in cartilage tissue were decreased (P<0.05). Compared with the model group, the symptoms of cartilage tissue degeneration in knee joint of rabbits were alleviated, scores of local pain, gait, joint activity and joint swelling, the modified Mankin's score, apoptosis rate, serum levels of IL-18 and IL-6, and the expression of LC3Ⅱ/LC3Ⅰand Beclin-1, Bax, Cleaved Caspase-3, BNIP3 proteins in cartilage tissue were decreased in the cryptotanshinone group, and the serum level of IL-10 and the expression of HIF-1α protein in cartilage tissue were obviously increased (P<0.05). There was no obvious changes in all indicators of rabbits in the empty group (P>0.05). Compared with the cryptotanshinone group, the symptoms of cartilage tissue degeneration in knee joint of rabbits worsened in the cryptotanshinone+HIF-1α knockdown group, and scores of local pain, gait, joint activity and joint swelling, the modified Mankin's score, apoptosis rate, serum levels of IL-18 and IL-6 and the expression of LC3Ⅱ/LC3Ⅰand Beclin-1, Bax, Cleaved Caspase-3, BNIP3 proteins in cartilage tissue were increased, the level of serum IL-10 and the expression of HIF-1α protein in cartilage tissue were decreased (P<0.05). Changes were opposite to those of the HIF-1α knock-down group. Conclusion Cryptotanshinone can up-regulate HIF-1α to down-regulate BNIP3 expression, inhibit inflammation and autophagy, reduce the degeneration of knee joint cartilage tissue in KOA rabbits, and improve its clinical symptoms.

Key words: cryptotanshinone, osteoarthritis, knee, chondrocytes, autophagy, apoptosis, HIF-1α/BNIP3

中图分类号:

R285.5

图/表 9

表1 各组兔膝关节临床症状局部疼痛、步态、关节活动及关节肿胀评分比较（n=9，分，$\bar{x}±s$）

Tab.1 Comparison of score of local pain, gait, joint activity and joint swelling in clinical symptoms of knee joints of rabbits between six groups

组别	局部疼痛	步态	关节活动	关节肿胀
对照组	0（0，0）	0（0，0）	0（0，0）	0（0，0）
模型组	2（2，2）^a	2（2，2）^a	2（2，2）^a	1（1，1）^a
空载组	2（2，2）	2（2，2）	2（2，2）	1（1，1）
隐丹参酮组	0（0，1）^b	0（0，1）^b	0（0，1）^b	0（0，0）^b
HIF-1α敲低组	3（2，3）^b	3（3，3）^b	3（2，3）^b	2（2，2）^b
隐丹参酮+ HIF-1α敲低组	2（1，2）^cd	2（1，2）^cd	1（1，2）^cd	1（1，1）^cd
H	125.441^＊	135.052^＊	172.203^＊	109.246^＊

图1 各组兔膝关节软骨组织的软骨退变情况检测（HE染色，×200）

Fig.1 Cartilage degeneration in knee joint cartilage tissue of rabbits in each group (HE staining, ×200)

图2 各组兔膝关节软骨组织细胞凋亡情况检测（TUNEL染色，×200）

Fig.2 Apoptosis in knee joint cartilage tissue of rabbits in each group (TUNEL staining, ×200)

表2 各组兔膝关节软骨组织改良Mankin's评分和细胞凋亡率比较（n=9，$\bar{x}±s$）

Tab.2 Comparison of modified Mankin's score and cell apoptosis rate of rabbit knee joint cartilage tissue between the six groups

组别	改良Mankin's评分/分	凋亡率/%
对照组	0（0，0）	1.14±0.33
模型组	3（3，3）^a	38.26±5.31^a
空载组	3（3，3）	39.13±5.46
隐丹参酮组	1（0，1）^b	3.45±0.62^b
HIF-1α敲低组	4（4，4）^b	56.74±8.10^b
隐丹参酮+HIF-1α敲低组	2（2，3）^cd	34.83±6.05^cd
H或F	145.365^＊	162.700^＊

表3 各组兔血清炎性因子IL-18、IL-6、IL-10水平比较（n=9，ng/L，$\bar{x}±s$）

Tab.3 Comparison of serum levels of inflammatory cytokines IL-18, IL-6 and IL-10 between six groups of rabbits

组别	IL-18	IL-6	IL-10
对照组	310.25±34.32	126.18±21.32	52.33±9.21
模型组	984.63±89.57^a	453.84±57.19^a	23.86±3.57^a
空载组	958.56±92.43	464.53±62.45	21.02±4.13
隐丹参酮组	332.42±38.21^b	141.25±25.21^b	45.11±9.42^b
HIF-1α敲低组	1 564.82±162.55^b	821.39±86.53^b	3.45±0.64^b
隐丹参酮+ HIF-1α敲低组	856.71±91.39^cd	430.72±60.47^cd	25.24±3.96^cd
F	219.800^＊	182.100^＊	76.740^＊

图3 蛋白免疫印迹实验检测各组兔膝关节软骨组织自噬和凋亡相关蛋白的表达 A：对照组；B：模型组；C：空载组；D：隐丹参酮组；E：HIF-1α敲低组；F：隐丹参酮+HIF-1α敲低组；图4同。

Fig.3 Autophagy and apoptosis related protein expression in knee joint cartilage tissue of rabbits in each group detected by Western blot assay

表4 各组兔膝关节软骨组织自噬和凋亡相关蛋白表达水平比较（n=9，$\bar{x}±s$）

Tab.4 Comparison of relative expression of autophagy and apoptosis related protein in knee joint cartilage tissue of rabbits between six groups

组别	LC3Ⅱ/LC3Ⅰ	Beclin-1	Bax	Cleaved Caspase-3
对照组	0.11±0.02	0.14±0.02	0.20±0.05	0.27±0.06
模型组	0.52±0.07^a	0.59±0.10^a	0.65±0.12^a	0.78±0.14^a
空载组	0.53±0.08	0.60±0.11	0.66±0.13	0.79±0.13
隐丹参酮组	0.13±0.04^b	0.16±0.03^b	0.23±0.06^b	0.30±0.07^b
HIF-1α敲低组	0.94±0.13^b	0.99±0.14^b	1.10±0.17^b	1.26±0.20^b
隐丹参酮+HIF-1α敲低组	0.49±0.09^cd	0.56±0.07^cd	0.61±0.16^cd	0.73±0.18^cd
F	132.800^＊	114.300^＊	64.560^＊	61.920^＊

图4 蛋白免疫印迹实验检测各组兔膝关节软骨组织HIF-1α/BNIP3通路相关蛋白的表达

Fig.4 HIF-1α/BNIP3 pathway related protein expression in knee joint cartilage tissue of rabbits in each group detected by Western blot assay

表5 各组兔膝关节软骨组织HIF-1α/BNIP3通路相关蛋白表达水平比较（n=9，$\bar{x}±s$）

Tab.5 Comparison of relative expression of HIF-1α/BNIP3 pathway related protein in knee joint cartilage tissue of rabbits between six groups

组别	HIF-1α	BNIP3
对照组	1.16±0.12	0.17±0.04
模型组	0.57±0.06^a	0.62±0.09^a
空载组	0.55±0.07	0.64±0.11
隐丹参酮组	1.11±0.15^b	0.19±0.05^b
HIF-1α敲低组	0.12±0.03^b	1.07±0.16^b
隐丹参酮+HIF-1α敲低组	0.61±0.08^cd	0.59±0.14^cd
F	156.300^＊	86.860^＊

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隐丹参酮调节HIF-1α/BNIP3信号通路对兔膝骨关节炎模型软骨细胞自噬和凋亡的影响

Impacts of cryptotanshinone on autophagy and apoptosis of chondrocytes in rabbit model of knee osteoarthritis by regulating HIF-1α/BNIP3 signaling pathway

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