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中华关节外科杂志(电子版) ›› 2022, Vol. 16 ›› Issue (06) : 683 -689. doi: 10.3877/cma.j.issn.1674-134X.2022.06.006

临床论著

小核仁RNA宿主基因7和微小RNA-449a在膝骨关节炎的表达
谭钝1, 蔡慧1, 李贵求1, 苏飞军1, 潘祺1, 雷毅1, 童作明1,†()   
  1. 1. 417000　娄底市中心医院骨科
  • 收稿日期:2022-03-29 出版日期:2022-12-01
  • 通信作者: 童作明
  • 基金资助:
    娄底市应用技术研究与开发项目(娄财教指〔2019〕61号)

Expression of small nucleolar RNA host gene 7 and microRNA-449A in knee osteoarthritis

Dun Tan1, Hui Cai1, Guiqiu Li1, Feijun Su1, Qi Pan1, Yi Lei1, Zuoming Tong1,†()   

  1. 1. Department of Orthopedics, Loudi Central Hospital, Loudi 417000, China
  • Received:2022-03-29 Published:2022-12-01
  • Corresponding author: Zuoming Tong
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引用本文：

谭钝, 蔡慧, 李贵求, 苏飞军, 潘祺, 雷毅, 童作明. 小核仁RNA宿主基因7和微小RNA-449a在膝骨关节炎的表达[J]. 中华关节外科杂志(电子版), 2022, 16(06): 683-689.

Dun Tan, Hui Cai, Guiqiu Li, Feijun Su, Qi Pan, Yi Lei, Zuoming Tong. Expression of small nucleolar RNA host gene 7 and microRNA-449A in knee osteoarthritis[J]. Chinese Journal of Joint Surgery(Electronic Edition), 2022, 16(06): 683-689.

目的

探讨长链非编码RNA(lncRNA)小核仁RNA宿主基因7(SNHG7)、微小RNA(miRNA)-449a在膝骨关节炎患者血清中的表达情况，分析其与疾病活动评分及骨密度(BMD)的关系。

方法

选取2019年7月至2021年6月在娄底市中心医院骨科就诊并确诊为膝骨关节炎患者168例为观察组，排除痛风、风湿性关节炎、自身免疫性疾病、既往膝关节严重创伤史等。另外选取与患者性别和年龄匹配的健康体检志愿者100例为对照组。采用反转录(RT)-PCR法检测各组血清中lncRNA SNHG7、miR-449a表达水平；Pearson法分析lncRNA SNHG7、miR-449a与疾病活动评分及BMD的相关性；受试者工作特征(ROC)曲线分析血清lncRNA SNHG7、miR-449a水平诊断膝骨关节炎患者的价值。

结果

膝骨关节炎患者血清中miR-449a表达水平高于对照组，且随着Kellgren-Lawrence(K-L)分级增加而升高(t＝9.354，P<0.05)，lncRNA SNHG7表达水平低于对照组，随着KL分级增加而降低(t＝18.321，P<0.05)；不同KL分级患者的视觉模拟量表(VAS)评分、膝关节学会评分系统(KSS)评分比较差异无统计学意义(均为P>0.05)；与对照组相比，膝骨关节炎患者全身BMD、腰椎BMD、髋关节BMD、股骨BMD均下降，差异有统计学意义(t＝6.608、5.568、7.861、6.097，均为P<0.05)；Pearson法分析结果显示，膝骨关节炎患者血清中lncRNA SNHG7、miR-449a表达呈明显负相关(r＝－0.330，P<0.05)；膝骨关节炎患者血清中lncRNA SNHG7水平与BMD(包括全身、腰椎、髋关节、股骨)呈正相关，与西安大略和麦克马斯特大学骨关节炎调查量表(WOMAC)评分呈负相关(r＝0.177、0.247、0.175、0.371、－0.385，均为P<0.05)，miR-449a水平与BMD(包括全身、腰椎、髋关节、股骨)呈负相关，与WOMAC评分呈正相关(r＝－0.167、－0.295、－0.277、－0.216、－0.275，均为P<0.05)。ROC曲线结果显示，血清lncRNA SNHG7、miR-449a水平诊断膝骨关节炎的曲线下面积(AUC)分别为0.947[95%置信区间(CI)(0.913，0.970)]、0.817[95%CI(0.766，0.862)]，对应的敏感度分别为91.1%、70.8%，特异度分别为89.0%、86.0%。血清lncRNA SNHG7、miR-449a水平联合诊断膝骨关节炎患者的AUC为0.966[95%CI(0.937，0.984)]，敏感度为92.3%，特异度为89.0%。

结论

lncRNA SNHG7在膝骨关节炎患者血清中表达下调，miR-449a表达上调，二者与患者疾病活动评分和BMD密切相关。

关键词: 膝, 骨关节炎, RNA，长链非编码, RNA，小核仁, 微RNAs, 骨密度
Objective

To investigate the expressions of long non-coding RNA (lncRNA) small nucleolar RNA host gene 7 (SNHG7) and microRNA(miR)-449a in the serum of knee osteoarthritis patients, and to analyze their relationships with disease activity scores and bone mineral density (BMD).

Methods

A total of 168 patients diagnosed with knee osteoarthritis in the Department of Orthopedics, Loudi Central Hospital from July 2019 to June 2021 were selected as the observation group, excluding gout, rheumatoid arthritis, autoimmune diseases, and previous history of severe knee trauma. In addition, 100 healthy volunteers matching the gender and age of the patients were selected as the control group. The expression levels of lncRNA SNHG7 and miR-449a in serum of each group were detected by reverse transcription (RT)-PCR; the correlation of lncRNA SNHG7 and miR-449a with disease activity score and bone mineral density (BMD) was analyzed by Pearson method; the value of serum lncRNA SNHG7 and miR-449a levels in the diagnosis of patients with knee osteoarthritis was analyzed by receiver operating characteristic (ROC) curve.

Results

The expression level of miR-449a in serum of patients with knee osteoarthritis was higher than that of the control group, and increased with the increase of Kellgren-Lawrence(K-L) grade (t=9.354, P<0.05); the expression level of lncRNA SNHG7 was lower than that of the control group, and decreased with the increase of K-L grade (t=18.321, P<0.05). There was no statistically significant difference in visual analog scale (VAS) or the Knee Society score(KSS) of the patients with different K-L grades (both P>0.05). Compared with the control group, the BMD of whole body, lumbar spine, hip and femur of knee osteoarthritis patients decreased, and the differences were statistically significant (t=6.608, 5.568, 7.861, 6.097, all P<0.05). The results of Pearson analysis showed that the expressions of lncRNA SNHG7 and miR-449a in the serum of knee osteoarthritis patients were negatively correlated (r=-0.330, P<0.05). The level of lncRNA SNHG7 in the serum of knee osteoarthritis patients was positively correlated with BMD (including whole body, lumbar spine, hip and femur), and negatively correlated with Western Ontario and McMaster Universities arthritis index (WOMAC) (r=0.177, 0.247, 0.0.175, 0.371, -0.385, all P<0.05). The level of miR-449a was negatively correlated with BMD (including whole body, lumbar spine, hip and femur), and positively correlated with WOMAC score (r=-0.167, -0.295, -0.277, -0.216, -0.275, all P<0.05). The ROC curve results showed that the areas under the curve (AUCs) of serum lncRNA SNHG7 and miR-449a levels in the diagnosis of knee osteoarthritis were 0.947 [95% confidence interval (CI)(0.913, 0.970) ] and 0.817[95%CI(0.766, 0.862)] respectively, the sensitivities were 91.1% and 70.8%, and the specificities were 89.0% and 86.0%. The AUC of serum lncRNA SNHG7 combined miR-449a to diagnose patients with knee osteoarthritis was 0.966 [95%CI(0.937, 0.984)], with a sensitivity of 92.3% and a specificity of 89.0%.

Conclusion

The expression of lncRNA SNHG7 is down-regulated in the serum of patients with knee osteoarthritis, and the expression of miR-449a is up-regulated; these two are closely related to the disease activity score and BMD of patients.

Key words: Knee, Osteoarthritis, RNA, long non-coding, RNA, small nucleolar, MicroRNAs, Bone mineral density
图1 膝骨关节炎患者不同Kellgren-Lawrence分级的膝骨关节典型图片示例注：Ⅰ级(有轻微骨赘)；Ⅱ级(有明显骨赘，并有关节间隙狭窄)；Ⅲ级(关节间隙中度狭窄)；Ⅳ级(关节间隙明显狭窄，严重骨质硬化)
表1 实时荧光定量PCR引物序列
基因名称 正向引物5’-3’ 反向引物5’-3’
lncRNA SNHG7 GTGACTTCGCCTGTGATGGA GGCCTCTATCTGTACCTTTATTCC
GAPDH AACGTGTCAGTGGTGGACCTG AGTGGGTGTCGCTGTTGAAGT
miR-449a TGCGGTGGCAGTGTATTGTTAGC CCAGTGCAGGGTCCGAGGT
U6 GCTCGCTTCGGCAGCACA GAGGTATTCGCACCAGAGGA
表2 两组一般资料比较
参数 观察组 对照组 统计值 P值
例数 168 100
年龄[岁，(±s)] 55.55±12.56 57.96±12.42 t＝1.526 >0.05
性别(男/女) 65/103 45/55 χ2＝1.013 >0.05
身高[cm, (±s)] 158.62±6.88 157.69±7.98 t＝1.007 >0.05
体重[kg, (±s)] 55.02±8.88 54.05±8.12 t＝0.893 >0.05
BMI[kg/m2, (±s)] 23.71±2.15 23.63±2.32 t＝0.286 >0.05
BMD[g/cm2，(±s)] 全身 0.76±0.14 0.93±0.28 t＝6.608 <0.001
腰椎 0.78±0.18 0.93±0.26 t＝5.568 <0.001
髋关节 0.71±0.18 0.95±0.32 t＝7.860 <0.001
股骨 0.72±0.24 0.92±0.29 t＝6.097 <0.001
WOMAC评分(±s) 113.31±12.46 0 － －
图2 各组患者血清中lncRNA SNHG7、miR-449a表达水平比较注：*-与观察组相比，P<0.05
图3 各组患者血清中lncRNA SNHG7、miR-449a表达水平比较注：lncRNA SNHG7-长链非编码RNA小核仁RNA宿主基因7; miR-微小RNA; a-与Ⅳ级患者相比，P<0.05；b-与Ⅲ级患者相比，P<0.05；c-与Ⅱ级患者相比，P<0.05
图4 各组患者VAS(视觉模拟评分)和KSS(膝关节协会评分)水平比较注：a-与Ⅳ级患者相比，P<0.05；b-与Ⅲ级患者相比，P<0.05；c-与Ⅱ级患者相比，P<0.05
图5 膝骨关节炎患者血清中lncRNA SNHG7、miR-449a表达相关性分析注：lncRNA SNHG7-长链非编码RNA小核仁RNA宿主基因7; miR-微小RNA
表3 膝骨关节炎患者血清中lncRNA SNHG7、miR-449a与各指标的相关性
参数 lncRNA SNHG7 miR-449a
r P值 r P值
全身BMD 0.177 0.022 －0.167 0.030
腰椎BMD 0.247 0.001 －0.295 <0.001
髋关节BMD 0.175 0.023 －0.277 <0.001
股骨BMD 0.371 <0.001 －0.216 0.005
WOMAC评分 －0.385 <0.001 0.275 <0.001
图6 血清lncRNA SNHG7、miR-449a水平诊断膝骨关节炎的ROC(受试者工作特征)曲线注：lncRNA SNHG7-长链非编码RNA小核仁RNA宿主基因7; miR-微小RNA
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