创伤后骨关节炎模型大鼠血浆中microRNA特征组学研究

doi:10.3877/cma.j.issn.2096-0263.2025.05.001

目的

本研究着重研究了创伤后骨关节炎（PTOA）大鼠模型血浆中微小核糖核酸（MicroRNA）的表达谱差异，并通过生物信息学分析试图阐明microRNA在PTOA疾病发生发展过程中的作用。

方法

从9只两个月大的雌性Sprague-Dawley大鼠中采集血液样本，并对微小核糖核酸（miRNAs）进行测序。这些大鼠被分为三组：正常对照组（K组：无干预），手术诱导的轻度创伤后骨关节炎组（H组：改良Hulth模型手术后三周），以及手术诱导的重度创伤后骨关节炎组（J组：改良Hulth模型手术后五周）。利用实时荧光定量聚合酶链式反应（PCR）鉴定并验证了差异表达。确定了三组间的miRNA差异表达数据，并通过生物信息学分析进行了靶基因预测和通路分析。通过重组人白细胞介素1β（IL-1β）诱导建立了人膝关节骨关节炎样软骨细胞系。并利用逆转录聚合酶链式反应（RT-PCR）验证了差异表达的miRs是否在人膝关节软骨细胞和人膝关节骨关节炎样软骨细胞中差异表达。

结果

在H组和K组之间，miR-6315、miR-143-5p、miR-150-5p和miR-301b-3p的表达存在差异。其中，miR-6315、miR-150-5p和miR-301b-3p的表达上调，而miR-143-5p的表达下调。在J组和K组之间，miR-6315的表达上调且存在差异。然而，在H组和J组之间，miR-511-3p和miR-301a-3p的表达上调且存在差异。此外，在K组和H组（早期阶段）之间，miR-6315、miR-143-5p、miR-150-5p和miR-301b-3p的表达存在差异，这表明它们可以作为大鼠PTOA关节损伤的生物标志物。在J组中，miR-6315的表达也上调，这与上述结果一致。因此，miR-511-3p和miR-301a-3p可作为区分轻度和重度PTOA的生物标志物。其中，miR-143-5p、miR-150-5p和miR-301b-3p在人的膝关节骨关节炎软骨细胞和人的膝关节软骨细胞中也存在差异表达。特别是，miR-150-5p和miR-301b-3p的表达上调且具有统计学显著性。

结论

miR-6315、miR-143-5p、miR-150-5p、miR-301b-3p可用作大鼠PTOA关节损伤生物标志物。现在有必要对人体组织中的这些特定分子进一步进行研究，以检查它们作为人类PTOA损伤生物标志物的潜在适用性。

关键词: 创伤后骨关节炎, MicroRNAs, 生物标志物, 组学

Objective

This study focused on analyzing the differential expression profiles of microRNAs in the plasma of a rat model with post-traumatic osteoarthritis (PTOA) and aimed to elucidate the role of microRNAs in the pathogenesis and progression of PTOA through bioinformatics analysis.

Methods

Blood samples were collected from nine two-month-old female Sprague-Dawley rats, and microRNAs (miRNAs) were sequenced. The rats were divided into three groups: a normal control group (Group K: no intervention), a mild PTOA group induced by surgery (Group H: modified Hulth model at three weeks post-surgery), and a severe PTOA group induced by surgery (Group J: modified Hulth model at five weeks post-surgery). Differential miRNA expression was identified and validated using quantitative real-time polymerase chain reaction (qPCR). Bioinformatics analysis was performed to predict target genes and analyze associated pathways. A human knee osteoarthritis-like chondrocyte model was established by stimulating chondrocytes with recombinant human interleukin-1β (IL-1β). Reverse transcription PCR (RT-PCR) was used to verify whether the differentially expressed miRNAs were also differentially expressed in human knee chondrocytes and human knee osteoarthritis-like chondrocytes.

Results

Differential expression was observed between Group H and Group K for miR-6315, miR-143-5p, miR-150-5p, and miR-301b-3p. Among these, miR-6315, miR-150-5p, and miR-301b-3p were upregulated, while miR-143-5p was down regulated. Between Group J and Group K, miR-6315 was significantly upregulated. However, between Group H and Group J, miR-511-3p and miR-301a-3p were upregulated and showed differential expression. Furthermore, in the comparison between Group K and Group H (early stage), miR-6315, miR-143-5p, miR-150-5p, and miR-301b-3p exhibited differential expression, suggesting their potential as biomarkers for joint injury in rat PTOA. In Group J, miR-6315 was also upregulated, consistent with the above findings. Thus, miR-511-3p and miR-301a-3p may serve as biomarkers to distinguish between mild and severe PTOA. Notably, miR-143-5p, miR-150-5p, and miR-301b-3p were differentially expressed in human knee osteoarthritis chondrocytes compared to normal human knee chondrocytes, with miR-150-5p and miR-301b-3p showing significant upregulation.

Conclusion

miR-6315, miR-143-5p, miR-150-5p, and miR-301b-3p may serve as biomarkers for joint injury in rat PTOA. Further investigation in human tissues is warranted to evaluate their potential applicability as biomarkers for PTOA in humans.

Key words: Post-traumatic osteoarthritis, MicroRNAs, Biomarkers, Omics

表1 RT-PCR的前引物序列和后引物序列

基因名称	引物序列
Col2	F：5′-CCAGATGACCTTCCTACGCC-3′
Col2	R：5′-TTCAGGGCAGTGTACGTGAAC-3′
MMP-13	F：5′-TCCTGATGTGGGTGAATACAATG-3′
MMP-13	R：5′-GCCATCGTGAAGTCTGGTAAAAT-3′
β-actin	F：5′-TGGAACGGTGAAGGTGACAG-3′
β-actin	R：5′-AACAACGCATCTCATATTTGGAA-3′
miR-143-5p	F：5′-AATTATGGTGCAGTGCTGCATCTCT-3′
miR-150-5p	F：5′-TGCTCTCCCAACCCTTGTACCA -3′
miR-301b-3p	F：5′-CGCAGTGCAATGATATTGTCAAAGC-3′

表1 RT-PCR的前引物序列和后引物序列

基因名称	引物序列
Col2	F：5′-CCAGATGACCTTCCTACGCC-3′
Col2	R：5′-TTCAGGGCAGTGTACGTGAAC-3′
MMP-13	F：5′-TCCTGATGTGGGTGAATACAATG-3′
MMP-13	R：5′-GCCATCGTGAAGTCTGGTAAAAT-3′
β-actin	F：5′-TGGAACGGTGAAGGTGACAG-3′
β-actin	R：5′-AACAACGCATCTCATATTTGGAA-3′
miR-143-5p	F：5′-AATTATGGTGCAGTGCTGCATCTCT-3′
miR-150-5p	F：5′-TGCTCTCCCAACCCTTGTACCA -3′
miR-301b-3p	F：5′-CGCAGTGCAATGATATTGTCAAAGC-3′

图2 番红O-固绿染色揭示大鼠PTOA软骨基质进行性退变；（A）正常组：软骨结构完整，软骨细胞柱状排列密集；番红O阳性区域（蛋白多糖，PG）丰富均匀；潮线清晰锐利；（B）轻度PTOA组：软骨表面不规则，细胞排列紊乱伴早期减少；PG区域性减少（固绿染色增强）；潮线连续但模糊；（C）重度PTOA组：软骨表面粗糙缺损，细胞显著减少伴团簇化；PG严重耗竭（异质性染色缺失）；潮线断裂溶解

表2 样本序列统计表

样本	标记样本	原始数据的序列数量	经过过滤后（核苷酸长度≥18个）的序列数量
H_1	H01	19 998 220	17 638 112
H_2	H02	17 732 266	15 982 779
H_3	H03	21 530 981	20 203 192
J_1	J01	18 307 518	15 406 947
J_2	J02	23 070 592	18 564 898
J_3	J03	17 812 766	12 526 674
K_1	K01	16 679 203	14 434 621
K_2	K02	17 916 836	15 973 317
K_3	K03	24 615 965	19 761 342

表2 样本序列统计表

样本	标记样本	原始数据的序列数量	经过过滤后（核苷酸长度≥18个）的序列数量
H_1	H01	19 998 220	17 638 112
H_2	H02	17 732 266	15 982 779
H_3	H03	21 530 981	20 203 192
J_1	J01	18 307 518	15 406 947
J_2	J02	23 070 592	18 564 898
J_3	J03	17 812 766	12 526 674
K_1	K01	16 679 203	14 434 621
K_2	K02	17 916 836	15 973 317
K_3	K03	24 615 965	19 761 342

图3 H/J/K组样本唯一读段（Unique Reads）的RNA分类注释占比分布（多方法重复比对）：基于多方法重复比对，揭示H（H01-H03）、J（J01-J03）、K（K01-K03）三组样本中各RNA类别唯一读段占比特征。结果显示：无注释RNA（unknown）占比最高（均>40%），piRNA（15%~25%）为主要注释类型，miRNA（known+novo，合计5%~10%）次之，其余RNA（tRNA等）占比<5%；三组注释格局高度一致，提示RNA组成稳定性注：横坐标为样本名称，纵坐标为注释到各种RNA的去重序列占总的去重序列的比例， H：轻度PTOA组，J：重度PTOA组，K：正常组

表3 小RNA分类统计表（唯一注释）

Type	known iRNA	piRNA	rRNA	tRNA	snRNA	snoRNA	repeat	exon	intron	novo miRNA	unknown
H01	14 036	32 529	879	1 932	39	1180	121	23 521	11 607	176	60 955
H02	15 191	66 220	1 238	1 753	33	1162	127	29 579	14 082	196	83 351
H03	14 226	44 404	873	1 561	35	1385	113	23 134	11 646	143	64 241
J01	13 468	33 356	638	1 693	26	1111	180	23 102	11 780	187	60 067
J02	13 900	34 493	485	1 236	20	795	93	21 805	11 084	192	56 355
J03	10 455	48 616	1 283	2 533	71	2095	481	27 231	15 702	169	81 766
K01	14 195	37 282	429	873	19	395	73	19 258	9 923	185	51 683
K02	15 348	43 548	1 179	2 153	33	689	146	33 810	16 024	257	80 281
K03	13 420	44 968	866	2 091	62	2306	337	29 085	18 567	196	81 059

表3 小RNA分类统计表（唯一注释）

Type	known iRNA	piRNA	rRNA	tRNA	snRNA	snoRNA	repeat	exon	intron	novo miRNA	unknown
H01	14 036	32 529	879	1 932	39	1180	121	23 521	11 607	176	60 955
H02	15 191	66 220	1 238	1 753	33	1162	127	29 579	14 082	196	83 351
H03	14 226	44 404	873	1 561	35	1385	113	23 134	11 646	143	64 241
J01	13 468	33 356	638	1 693	26	1111	180	23 102	11 780	187	60 067
J02	13 900	34 493	485	1 236	20	795	93	21 805	11 084	192	56 355
J03	10 455	48 616	1 283	2 533	71	2095	481	27 231	15 702	169	81 766
K01	14 195	37 282	429	873	19	395	73	19 258	9 923	185	51 683
K02	15 348	43 548	1 179	2 153	33	689	146	33 810	16 024	257	80 281
K03	13 420	44 968	866	2 091	62	2306	337	29 085	18 567	196	81 059

图4 不同病理状态样本中miRs表达丰度的Upset图分析：基于Reads Count统计展示轻度PTOA组（H）、重度PTOA组（J）与正常组（K）的样本特异性及共有miRs数量分布：横坐标独立横条为各样本特有miRNA；连线与节点为样本共有miRNAnumber in each set表示每个样本鉴定到的全部miRNA的数目；number of each intersection表示多个样本鉴定到的共有miRNA的数目；横坐标一个点表示该样本鉴定到的特有miRNA的数目；横坐标多个点连线表示连线的多个样本鉴定到的共有miRNA的数目；H：轻度PTOA组，J：重度PTOA组，K：正常组

图5 通过密度图（A）和小提琴图（B）联合呈现不同样本（H组轻度PTOA、J组重度PTOA、K组正常组）中miRs表达密度在log₁₀（CPM）下的分布特征，其中密度图显示各组数据呈右偏态分布且中低表达miRs占主导、中高表达区间略现组间分离趋势，小提琴图则直观展现三组miRs表达密度的集中趋势、离散程度及低/中高表达区间的密度差异，共同反映PTOA不同严重程度与正常组的miRs表达模式共性与组间特征注：（A）密度直方图：横坐标：基因的log₁₀（CPM）值；纵坐标：对应表达水平的miRNA分布密度（B）小提琴图：箱体中间水平线：中位数；箱体上下边缘：第75百分位数；数据范围极限：第90百分位数；外部曲线：核密度估计曲线；H：轻度PTOA组，J：重度PTOA组，K：正常组

图6 不同PTOA组别及正常组样本间皮尔逊相关系数聚类分析图：颜色标尺：橙色越深表示相关性越高，数值范围0.71~1.00；左侧及上侧为样本聚类树状图，右侧及下侧标注样本名称注：图表左侧和上方：样本聚类结果；图表右侧和底部：样本名称标注；不同颜色方块：表示两两样本间的相关性强度（颜色深浅或色系差异映射相关系数绝对值大小）；H：轻度PTOA组，J：重度PTOA组，K：正常组

图7 展示了正常组（K）、轻度PTOA组（H）与重度PTOA组（J）间差异表达miRs的数量分布及表达趋势，其中JvsH（重度vs轻度）显示2个miRs上调、0个下调，反映疾病严重程度进展中的单向调控差异；KvsH（正常vs轻度）显示3个miRs上调、1个下调，体现正常与轻度病变间的双向表达差异；KvsJ（正常vs重度）显示1个miRs上调、0个下调，揭示正常与重度病变间以上调为主的表达特征，提示miR表达异常随疾病进展趋向单一方向（上调）注：横坐标：差异分析的比较组别；纵坐标：差异基因数量；颜色编码：红色表示上调基因，绿色表示下调基因，H：轻度PTOA组，J：重度PTOA组，K：正常组

表4 表达差异分析结果统计

对照组	处理组	Up-regulated	Down-regulated	Total
K	J	1	0	1
J	H	2	0	2
K	H	3	1	4

表4 表达差异分析结果统计

对照组	处理组	Up-regulated	Down-regulated	Total
K	J	1	0	1
J	H	2	0	2
K	H	3	1	4

图8 差异表达miRs双向聚类分析热图（基于欧氏距离与最长距离法）显示：样本聚类中，正常组（K）样本（K1、K2）高度同源，仅K3略异质，轻度PTOA组（H）样本表达模式相似，重度PTOA组（J）样本独立成簇且与H、K组差异显著；miRs聚类形成多簇功能模块，顶端红簇对应J组高表达miRs，中部绿簇在H组特异性高表达，底部蓝绿簇在K组富集，组内对角线深色块强化样本共享表达特征；不同组间miRs差异表达具特异性，该方法整合样本相似性与miRs共表达模式，揭示PTOA进程中miRs的差异化调控网络注：水平方向：miRNA序列排列；垂直方向：每列对应一个样本；颜色编码：红色表示高表达miRNA，绿色表示低表达miRNA。H：轻度PTOA组，J：重度PTOA组，K：正常组

图9 差异表达miRs预测靶基因的GO富集分析柱状图：不同PTOA组别（轻度、重度）与正常组差异表达miRs预测靶基因的GO富集分析柱状图（注：柱状图颜色代表GO类别：红色-细胞组分（CC），绿色-分子功能（MF），蓝色-生物过程（BP）；纵坐标为富集显著性-log₁₀（P-value），值越大表明富集程度越高）注：（A）J vs H；（B）K vs H；（C）K vs J；横坐标：GO第二层术语；纵坐标：各术语的-log（p值）富集度；H：轻度PTOA组，J：重度PTOA组，K：正常组

图10 不同PTOA组别（J为重度PTOA组、H为轻度PTOA组、K为正常组）与正常组及组间差异表达miRs靶基因的KEGG富集分析气泡图，筛选FDR值最小的前20条通路，以富集因子（RF）为横坐标、信号通路为纵坐标，通过气泡大小（富集基因数量）和颜色（FDR值，红色表示富集极显著、绿色表示富集不显著）展示富集显著性及基因数目注：（A）J vs H；（B）K vs H；（C）K vs J；H：轻度PTOA组，J：重度PTOA组，K：正常组

图11 人类OA与正常软骨中MMP13及col2的qRT-PCR表达差异：图A MMP13表达：OA组相对表达量显著高于正常组（P<0.05），提示IL-1β诱导的OA软骨细胞中，软骨基质降解关键酶MMP13呈高表达，符合OA病理中基质降解特征。图B col2表达：OA组相对表达量显著低于正常组（P<0.05），表明OA软骨细胞中基质主要结构蛋白col2合成减少，与OA基质合成障碍的病理表现一致注：A：MMP13；B：Ⅱ型胶原；显著性标记：*（P<0.05）；黑色柱状图：正常软骨组；灰色柱状图：人类骨关节炎软骨组

图12 大鼠差异表达miRs在人OA与正常软骨细胞系中的相对表达：图A miR-301b-3p：OA组表达量较正常组显著升高（1.0→2.8，P<0.05），提示其可能参与OA病理中的促炎/促降解过程。图B miR-150-5p：OA组表达量约为正常组1.6倍（1.0→1.6，P<0.05），其上调可能关联软骨细胞功能异常或基质降解通路激活。图C miR-143-5p：OA组表达量显著低于正常组（1.0→0.9，P<0.05），其下调可能影响软骨基质合成与修复能力注：A：miR-301b-3p；B：miR-150-5p；C：miR-143-5p；显著性标记：*（P<0.05）；黑色柱状图：正常软骨组；灰色柱状图：人类骨关节炎软骨组

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MicroRNA signature omics study in the blood of rats with post-traumatic osteoarthritis model

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MicroRNA signature omics study in the blood of rats with post-traumatic osteoarthritis model