甲状腺激素与骨关节炎的关联：来自孟德尔随机化和 RNA 测序分析。

Association of thyroid hormone with osteoarthritis: from mendelian randomization and RNA sequencing analysis.

机构信息

Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Zhong Shan 2nd Road, No. 58, Guangzhou, 510080, Guangdong, China.

Department of Nosocomial Infection, The First Affiliated Hospital, Sun Yat-Sen University, Zhong Shan 2nd Road, No. 58, Guangzhou, 510080, Guangdong, China.

出版信息

J Orthop Surg Res. 2024 Jul 25;19(1):429. doi: 10.1186/s13018-024-04939-x.

DOI:10.1186/s13018-024-04939-x

PMID:39054551

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11270794/

Abstract

BACKGROUND

The relationship between thyroid hormone (TH) levels in vivo and osteoarthritis (OA) remains inconclusive. This study aims to investigate the association between TH levels and OA, analyze the effect of triiodothyronine on hypertrophic chondrocyte differentiation and OA progression, and identify potential target genes of triiodothyronine in OA to evaluate its diagnostic value.

METHODS

Two-sample mendelian randomization method was used to probe the causal links between hyperthyroidism and OA. Differentially expressed genes (DEGs) from two RNA-sequencing data in Gene Expression Omnibus (GSE199847 and GSE114007) and enrichment analysis of DEGs (166 commonly upregulated genes and 71 commonly downregulated genes of GSE199847 and GSE114007) was performed to analyze the effect of triiodothyronine (T3) on hypertrophic chondrocyte differentiation and OA. C28/I2 cells treated with T3 and reverse transcription and quantitative real-time polymerase chain reaction were used to validate T3 targeted genes. The diagnostic performance of target genes was assessed by the receiver operating characteristic (ROC) curve and area under the curve (AUC).

RESULTS

There was a positive causal association between hyperthyroidism and OA (IVW result, OR = 1.330, 95% CI 1.136-1.557, P = 0.0004). Weighted median and Weighted mode analysis also demonstrated that hyperthyroidism had a positive causal association with OA (p < 0.05, OR > 1). Bioinformatics analysis indicated T3 can partially induce the emergence of late hypertrophic chondrocyte and promote OA through extracellular matrix organization, blood vessel development, skeletal system development and ossification. Post-T3 treatment, MAFB, C1QTNF1, COL3A1 and ANGPTL2 were significantly elevated in C28/I2 cells. ROC curves in GSE114007 showed that AUC of all above genes were ≥ 0.7.

CONCLUSIONS

This study identified that hyperthyroidism has a positive causal association with OA by MR analysis. T3 induced hypertrophic chondrocytes promote OA progression by upregulating genes such as MAFB, C1QTNF1, COL3A1 and ANGPTL2, which can also serve as OA diagnosis.

摘要

背景

体内甲状腺激素（TH）水平与骨关节炎（OA）之间的关系尚无定论。本研究旨在探讨 TH 水平与 OA 之间的关系，分析三碘甲状腺原氨酸（T3）对肥大软骨细胞分化和 OA 进展的影响，并鉴定 OA 中 T3 的潜在靶基因，以评估其诊断价值。

方法

采用两样本 Mendelian 随机化方法探讨甲状腺功能亢进症与 OA 之间的因果关系。对来自两个基因表达综合数据库（GSE199847 和 GSE114007）的 RNA 测序数据中的差异表达基因（DEGs）进行富集分析，并对 DEGs 进行分析（GSE199847 和 GSE114007 中 166 个共同上调基因和 71 个共同下调基因），以分析 T3 对肥大软骨细胞分化和 OA 的影响。采用 T3 处理 C28/I2 细胞，并进行逆转录和定量实时聚合酶链反应，以验证 T3 的靶向基因。采用受试者工作特征（ROC）曲线和曲线下面积（AUC）评估靶基因的诊断性能。

结果

甲状腺功能亢进症与 OA 之间存在正因果关系（IVW 结果，OR=1.330，95%CI1.136-1.557，P=0.0004）。加权中位数和加权模式分析也表明，甲状腺功能亢进症与 OA 之间存在正因果关系（p<0.05，OR>1）。生物信息学分析表明，T3 可部分诱导晚期肥大软骨细胞的出现，并通过细胞外基质组织、血管发育、骨骼系统发育和骨化来促进 OA。T3 处理后，C28/I2 细胞中 MAFB、C1QTNF1、COL3A1 和 ANGPTL2 明显升高。在 GSE114007 中的 ROC 曲线显示，所有上述基因的 AUC 值均≥0.7。