To characterize aspects of triiodothyronine (T3) induced chondrocyte terminal maturation within the molecular osteoarthritis pathophysiology using the previously established T3 human ex vivo osteochondral explant model. RNA-sequencing was performed on explant cartilage obtained from OA patients (n = 8), that was cultured ex vivo with or without T3 (10 ng/ml), and main findings were validated using RT-qPCR in an independent sample set (n = 22). Enrichment analysis was used for functional clustering and comparisons with available OA patient RNA-sequencing and GWAS datasets were used to establish relevance for OA pathophysiology by linking to OA patient genomic profiles. Besides the upregulation of known hypertrophic genes EPAS1 and ANKH, T3 treatment resulted in differential expression of 247 genes with main pathways linked to extracellular matrix and ossification. CCDC80, CDON, ANKH and ATOH8 were among the genes found to consistently mark early, ongoing and terminal maturational OA processes in patients. Furthermore, among the 37 OA risk genes that were significantly affected in cartilage by T3 were COL12A1, TNC, SPARC and PAPPA. RNA-sequencing results show that metabolic activation and recuperation of growth plate morphology are induced by T3 in OA chondrocytes, indicating terminal maturation is accelerated. The molecular mechanisms involved in hypertrophy were linked to all stages of OA pathophysiology and will be used to validate disease models for drug testing.

中文翻译：

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甲状腺激素在保存的 OA 软骨仿生模型中诱导骨化和终末成熟

使用先前建立的 T3 人离体骨软骨外植体模型来表征分子骨关节炎病理生理学中三碘甲腺原氨酸 (T3) 诱导的软骨细胞终末成熟的各个方面。对从 OA 患者 (n = 8) 获得的外植体软骨进行 RNA 测序，该软骨在有或没有 T3 (10 ng/ml) 的情况下离体培养，并使用 RT-qPCR 在独立样本集 (n = 8) 中验证了主要结果= 22）。富集分析用于功能聚类，并与可用的 OA 患者 RNA 测序和 GWAS 数据集进行比较，通过链接 OA 患者基因组谱来建立 OA 病理生理学的相关性。除了已知的肥大基因 EPAS1 和 ANKH 上调外，T3 处理还导致 247 个基因的差异表达，其主要途径与细胞外基质和骨化有关。 CCDC80、CDON、ANKH 和 ATOH8 等基因被发现一致标记患者早期、持续和终末成熟 OA 过程。此外，受 T3 显着影响的 37 个软骨中的 OA 风险基因包括 COL12A1、TNC、SPARC 和 PAPPA。 RNA测序结果表明，OA软骨细胞中T3诱导代谢激活和生长板形态恢复，表明终末成熟加速。肥大涉及的分子机制与 OA 病理生理学的所有阶段相关，并将用于验证药物测试的疾病模型。