膝骨关节炎中微小RNA-138与缺氧诱导因子-2α表达及意义

doi:10.3877/cma.j.issn.1674-134X.2021.02.010

目的

探究微小RNA-138(miR-138)、低氧诱导因子-2α(HIF-2α)在膝关节骨关节炎(KOA)患者滑膜及关节液中的表达情况及临床意义。

方法

选择2016年3月至2019年10月首都医科大学附属北京潞河医院诊治的KOA患者80例为KOA组，排除类风湿关节炎、强直性脊柱炎等免疫性疾病、合并其他类型的关节疾病、严重骨质疏松症，并选取同期本院收治的半月板损伤者76例作为对照组。检查两组滑膜、关节液miR-138、HIF-2α的表达水平，两组间比较采用t检验。分析不同Kellgren-Lawrence(K-L)分级KOA患者滑膜、关节液miR-138、HIF-2α的表达水平，多组间数据比较行单因素方差分析；Pearson法分析KOA患者滑膜及关节液中miR-138、HIF-2α表达水平的关系；分析滑膜和关节液miR-138、HIF-2α对KOA的诊断价值；检测正常软骨细胞、KOA软骨细胞中miR-138、HIF-2α表达水平；分析KOA软骨细胞中miR-138沉默/过表达对HIF-2α表达的影响。

结果

KOA患者滑膜、关节液及软骨细胞中miR-138表达水平均显著低于对照组(t＝8.324、9.054、2.613，均为P<0.05)，HIF-2α mRNA表达水平均显著高于对照组(t＝8.219、10.685、2.576，均为P<0.05)。Ⅲ、Ⅳ级组KOA患者滑膜、关节液中miR-138表达水平显著低于Ⅱ级组(t_Ⅲ-Ⅱ＝3.731、5.120、t_Ⅳ-Ⅱ＝7.878、10.511，均为P<0.05)，Ⅳ级组KOA患者滑膜、关节液中miR-138表达水平显著低于Ⅲ级组(t＝4.997、6.518，均为P<0.05)。Ⅲ、Ⅳ级组KOA患者滑膜、关节液中HIF-2α表达水平显著高于Ⅱ级组(t_Ⅲ-Ⅱ＝3.462、4.057，t_Ⅳ-Ⅱ＝5.731、6.528，均为P<0.05)，Ⅳ级组KOA患者滑膜、关节液中HIF-2α表达水平显著高于Ⅲ级组(t＝2.855、3.135，均为P<0.05)。滑膜、关节液miR-138诊断KOA的曲线下面积(AUC)分别为0.812、0.860，截断值分别为0.93、0.81，此时对应灵敏度分别为86.3%、81.3%，特异性为72.4%、81.6%。滑膜、关节液HIF-2α诊断KOA的AUC分别为0.890、0.881，截断值分别为1.43，1.44，此时对应灵敏度分别为81.3%、76.3%，特异性为85.5%、86.8%。miR-138、HIF-2α分别在滑膜、关节液中联合诊断KOA的AUC分别为0.924、0.929，灵敏度分别为87.5%、90.0%，对应特异度分别为90.8%、88.2%。miR-138-siRNA组miR-138表达水平均显著低于空白组、NC-siRNA组(t＝2.895、2.893，均为P<0.05)，HIF-2α mRNA表达水平显著高于空白组、NC-siRNA组(t＝2.861、2.717，均为P<0.05)；miR-138-mimics组miR-138表达水平显著高于空白组、NC-mimics组(t＝2.731、2.694,均为P<0.05)，HIF-2α mRNA表达水平显著低于空白组、NC-mimics组(t＝2.998、3.112，均为P<0.05)。

结论

KOA患者滑膜、关节液中miR-138呈低表达，HIF-2α呈高表达，两者在滑膜、关节液中存在负相关，miR-138可能通过调控HIF-2α进而参与KOA病变过程，且两者联合可有效提高诊断KOA的价值。

关键词: 膝, 骨关节炎, 微RNAs, 缺氧诱导因子1, α亚基

Objective

To investigate the expressions of microRNA-138 (miR-138) and hypoxia inducible factor-2α (HIF-2α) in synovial membrane and synovial fluid of patients with knee osteoarthritis (KOA) and their clinical significances.

Methods

From March 2016 to October 2019, 80 patients with KOA treated by Beijing Luhe Hospital Affiliated to Capital Medical University were treated as KOA group, excluding immune diseases such as rheumatoid arthritis, ankylosing spondylitis, joint diseases combined with other types, serious osteoporosis, and 76 cases of meniscus injury during the same period were selected as the control group. The expression levels of miR-138 and HIF-2α in synovium and synovial fluid of the two groups were examined, and compared by t test. The expression levels of miR-138 and HIF-2α in synovium and synovial fluid of KOA patients with different Kellgren-Lawrence(K-L) grades were compared by one-way ANOVA, and the Pearson method was used to analyze the relationship between the expression levels of miR-138 and HIF-2α in synovial membrane and synovial fluid of KOA patients. The diagnostic value of miR-138 and HIF-2α in synovial membrane and synovial fluid were analyzed. The expression levels of miR-138 and HIF-2α in normal chondrocytes and KOA chondrocytes were detected, and the effect of miR-138 silencing/overexpression on HIF-2α expression in KOA chondrocytes was analyzed.

Results

The expression of miR-138 in synovial membrane, synovial fluid and chondrocytes of KOA patients was significantly lower than that of control group (t=8.324, 9.054, 2.613, all P<0.05), and the expression of HIF-2α mRNA was significantly higher than that of control group (t=8.219, 10.685, 2.576, all P<0.05). The expression level of miR-138 in synovium membrane and synovial fluid of patients with grade III and IV KOA was significantly lower than that of patients with grade II KOA (t_Ⅲ-Ⅱ=3.731, 5.120, t_Ⅳ-Ⅱ=7.878, 10.511, all P<0.05). The expression level of miR-138 in synovium membrane and synovial fluid of patients with grade IV KOA was significantly lower than that of patients with grade III KOA (t =4.997, 6.518, all P<0.05); the expression level of HIF-2α in synovium membrane and synovial fluid of patients with grade III and IV KOA was significantly higher than that of patients with grade II KOA (t_Ⅲ-Ⅱ =3.462, 4.057, t_Ⅳ-Ⅱ =5.731, 6.528, both P<0.05). The expression of HIF-2α in synovium membrane and synovial fluid of patients with grade IV KOA was significantly higher than that of patients with grade III KOA (t =2.855, 3.135, both P<0.05); the areas under curve (AUC) of miR-138 in synovial membrane and synovial fluid for KOA diagnosis were 0.812 and 0.860, and the truncation values were 0.93 and 0.81, respectively. The corresponding sensitivities were 86.3%, 81.3%, and the specificities were 72.4% and 81.6%. The AUCs of HIF-2α in synovial membrane and synovial fluid in diagnosis of KOA were 0.890 and 0.881, and the cut-off values were 1.43 and 1.44, respectively. The corresponding sensitivities were 81.3%, 76.3%, and the specificities were 85.5% and 86.8%. The AUCs of miR-138 and HIF-2α in synovial membrane and synovial fluid were 0.924 and 0.929, respectively. The sensitivities were 87.5% and 90.0% respectively, and the corresponding specificities were 90.8% and 88.2% respectively; the expression level of miR-138 in miR-138-siRNA group was significantly lower than that in blank group and NC-siRNA group (t=2.895, 2.893, both P<0.05), HIF-2α mRNA expression level was significantly higher than that in blank group and NC-siRNA group (t=2.861, 2.717, both P<0.05); miR-138 expression level in miR-138-mimics group was significantly higher than that in blank group and NC-mimics group (t=2.731, 2.694, both P<0.05), and HIF-2α mRNA expression level was significantly lower than that in blank group and NC-mimics group (t=2.998, 3.112, both P<0.05).

Conclusions

The expression of miR-138 in synovium membrane and synovial fluid of the patients with KOA is low, and the expression of HIF-2α is high. There is a strong negative correlation between them, miR-138 may participate in the pathological process of KOA by regulating HIF-2α, and the combination of miR-138 and HIF-2α can effectively improve the diagnostic value of KOA.

Key words: Knee, Osteoarthritis, microRNAs, Hypoxia-inducible factor 1, alpha subunit

表1 miR-138、HIF-2α及对应内参U6、β-actin的引物序列

基因	正向引物5’-3’	反向引物5’-3’
miR-138	TCCGAGCCTGACTAAGTGTTGTGGTCGA	GTGCAGGTCCGAGGT
U6	CTCGCTTCGGCAGCACA	AACGCTTCACGAATTTGCGT
HIF-2α	GCACCAAGGGTCAGGTAGTAAG	CAGGTTGCGAGGGTTGTAGAT
β-actin	TGACGTGGACATCCGCAAAG	CTGGAAGGTGGACAGCGAGG

表1 miR-138、HIF-2α及对应内参U6、β-actin的引物序列

基因	正向引物5’-3’	反向引物5’-3’
miR-138	TCCGAGCCTGACTAAGTGTTGTGGTCGA	GTGCAGGTCCGAGGT
U6	CTCGCTTCGGCAGCACA	AACGCTTCACGAATTTGCGT
HIF-2α	GCACCAAGGGTCAGGTAGTAAG	CAGGTTGCGAGGGTTGTAGAT
β-actin	TGACGTGGACATCCGCAAAG	CTGGAAGGTGGACAGCGAGG

表2 两组一般资料比较

组别	例数	男/女(例)	年龄[岁，(±s)]	身体质量指数[kg/m², (±s)]
对照组	76	45/51	57.0±10.1	23.3±2.1
KOA组	80	47/33	56.9±9.6	23.9±2.3
统计值		χ²＝2.466	t＝0.063	t＝1.870
P值		0.116	0.949	0.063

表2 两组一般资料比较

组别	例数	男/女(例)	年龄[岁，(±s)]	身体质量指数[kg/m², (±s)]
对照组	76	45/51	57.0±10.1	23.3±2.1
KOA组	80	47/33	56.9±9.6	23.9±2.3
统计值		χ²＝2.466	t＝0.063	t＝1.870
P值		0.116	0.949	0.063

表3 两组滑膜、关节液中miR-138、HIF-2α表达水平比较(±s)

组别	例数	滑膜		关节液
组别	例数	miR-138	HIF-2α	miR-138	HIF-2α
对照组	76	1.10±0.32	0.98±0.29	1.05±0.30	1.08±0.31
KOA组	80	0.73±0.23	1.62±0.42	0.67±0.22	1.75±0.46
t值		8.324	11.020	9.054	10.612
P值		<0.001	<0.001	<0.001	<0.001

表3 两组滑膜、关节液中miR-138、HIF-2α表达水平比较(±s)

组别	例数	滑膜		关节液
组别	例数	miR-138	HIF-2α	miR-138	HIF-2α
对照组	76	1.10±0.32	0.98±0.29	1.05±0.30	1.08±0.31
KOA组	80	0.73±0.23	1.62±0.42	0.67±0.22	1.75±0.46
t值		8.324	11.020	9.054	10.612
P值		<0.001	<0.001	<0.001	<0.001

表4 不同K-L分级KOA患者滑膜、关节液中miR-138、HIF-2α表达水平比较(±s)

组别	例数	滑膜		关节液
组别	例数	miR-138	HIF-2α	miR-138	HIF-2α
Ⅱ级组	21	0.88±0.22	1.36±0.32	0.87±0.21	1.47±0.33
Ⅲ级组	35	0.74±0.20^a	1.60±0.35^a	0.69±0.19^a	1.78±0.39^a
Ⅳ级组	24	0.56±0.15^ab	1.79±0.39^ab	0.47±0.13^ab	2.01±0.44^ab
F值		15.768	8.219	27.955	10.685
P值		<0.001	<0.01	<0.001	<0.001

表4 不同K-L分级KOA患者滑膜、关节液中miR-138、HIF-2α表达水平比较(±s)

组别	例数	滑膜		关节液
组别	例数	miR-138	HIF-2α	miR-138	HIF-2α
Ⅱ级组	21	0.88±0.22	1.36±0.32	0.87±0.21	1.47±0.33
Ⅲ级组	35	0.74±0.20^a	1.60±0.35^a	0.69±0.19^a	1.78±0.39^a
Ⅳ级组	24	0.56±0.15^ab	1.79±0.39^ab	0.47±0.13^ab	2.01±0.44^ab
F值		15.768	8.219	27.955	10.685
P值		<0.001	<0.01	<0.001	<0.001

图1 KOA患者滑膜中miR-138与HIF-2α表达水平的关系

图2 KOA患者关节液中miR-138与HIF-2α表达水平的关系

图3 滑膜中miR(微小RNA)-138、HIF(低氧诱导因子)-2α表达水平对KOA(膝骨关节炎)的诊断价值

表5 滑膜和关节液miR-138、HIF-2α表达水平对KOA的诊断效能

滑膜指标	AUC(95%置信区间)	截断值	约登指数	灵敏度(%)	特异度(%)	准确度(%)	阳性似然比	阴性似然比	阳性预测值(%)	阴性预测值(%)
miR-138	0.812(0.741，0.883)	0.93	0.586	86.3	72.4	79.5	3.12	0.19	76.7	83.3
HIF-2α	0.890(0.840，0.944)	1.43	0.668	81.3	85.5	83.3	5.61	0.22	85.5	81.3
两者联合	0.924(0.881，0.958)		0.783	87.5	90.8	89.1	8.63	0.14	90.9	87.3
关节液指标	AUC(95%置信区间	截断值	约登指数	灵敏度(%)	特异度(%)	准确度(%)	阳性似然比	阴性似然比	阳性预测值(%)	阴性预测值(%)
miR-138	0.860(0.800，0.920)	0.81	0.628	81.3	81.6	81.4	4.42	0.23	82.3	80.5
HIF-2α	0.881(0.828，0.934)	1.44	0.631	76.3	86.8	81.4	5.80	0.27	85.9	77.6
两者联合	0.929(0.889，0.968)		0.782	90.0	88.2	89.1	7.60	0.11	88.9	89.3

表5 滑膜和关节液miR-138、HIF-2α表达水平对KOA的诊断效能

滑膜指标	AUC(95%置信区间)	截断值	约登指数	灵敏度(%)	特异度(%)	准确度(%)	阳性似然比	阴性似然比	阳性预测值(%)	阴性预测值(%)
miR-138	0.812(0.741，0.883)	0.93	0.586	86.3	72.4	79.5	3.12	0.19	76.7	83.3
HIF-2α	0.890(0.840，0.944)	1.43	0.668	81.3	85.5	83.3	5.61	0.22	85.5	81.3
两者联合	0.924(0.881，0.958)		0.783	87.5	90.8	89.1	8.63	0.14	90.9	87.3
关节液指标	AUC(95%置信区间	截断值	约登指数	灵敏度(%)	特异度(%)	准确度(%)	阳性似然比	阴性似然比	阳性预测值(%)	阴性预测值(%)
miR-138	0.860(0.800，0.920)	0.81	0.628	81.3	81.6	81.4	4.42	0.23	82.3	80.5
HIF-2α	0.881(0.828，0.934)	1.44	0.631	76.3	86.8	81.4	5.80	0.27	85.9	77.6
两者联合	0.929(0.889，0.968)		0.782	90.0	88.2	89.1	7.60	0.11	88.9	89.3

图4 关节液中miR(微小RNA)-138、HIF(低氧诱导因子)-2α表达水平对KOA(膝骨关节炎)的诊断价值

表6 不同软骨细胞中miR-138、HIF-2α表达水平比较(±s)

组别	样本数	miR-138	HIF-2α
正常软骨细胞	6	1.02±0.35	1.01±0.34
KOA软骨细胞	6	0.59±0.20	1.69±0.55
t值		2.613	2.576
P值		<0.05	<0.05

表6 不同软骨细胞中miR-138、HIF-2α表达水平比较(±s)

组别	样本数	miR-138	HIF-2α
正常软骨细胞	6	1.02±0.35	1.01±0.34
KOA软骨细胞	6	0.59±0.20	1.69±0.55
t值		2.613	2.576
P值		<0.05	<0.05

表7 KOA软骨细胞中miR-138沉默/过表达对HIF-2α表达的影响(±s)

组别	样本数	miR-138	HIF-2α
空白组	6	1.02±0.33	1.01±0.33
NC-siRNA组	6	1.03±0.34	1.04±0.35
miR-138-siRNA组	6	0.57±0.19^ab	1.82±0.61^ab
NC-mimics组	6	1.05±0.35	1.05±0.35
miR-138-mimics组	6	1.76±0.57^ac	0.55±0.18^ac
F值		7.726	8.257
P值		<0.001	<0.001

表7 KOA软骨细胞中miR-138沉默/过表达对HIF-2α表达的影响(±s)

组别	样本数	miR-138	HIF-2α
空白组	6	1.02±0.33	1.01±0.33
NC-siRNA组	6	1.03±0.34	1.04±0.35
miR-138-siRNA组	6	0.57±0.19^ab	1.82±0.61^ab
NC-mimics组	6	1.05±0.35	1.05±0.35
miR-138-mimics组	6	1.76±0.57^ac	0.55±0.18^ac
F值		7.726	8.257
P值		<0.001	<0.001

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Expression and significance of microRNA-138 and hypoxia-inducible factor-2α in knee osteoarthritis

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Expression and significance of microRNA-138 and hypoxia-inducible factor-2α in knee osteoarthritis