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. 2024 Apr 25;26(1):91.
doi: 10.1186/s13075-024-03326-5.

Thyroid hormone induces ossification and terminal maturation in a preserved OA cartilage biomimetic model

N M Korthagen  1 , E Houtman  1 , I Boone  1 , R Coutinho de Almeida  1 , K Sivasubramaniyan  2 , R Mahdad  3 , R G H H Nelissen  1 , Y F M Ramos  1 , M A Tessari  2 , I Meulenbelt  4
Affiliations

Thyroid hormone induces ossification and terminal maturation in a preserved OA cartilage biomimetic model

N M Korthagen et al. Arthritis Res Ther. .

Abstract

Objective: 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.

Designs: 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.

Results: 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.

Conclusions: 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.

Keywords: Cartilage; Chondrocyte; Hypertrophy; Lesioned; Osteochondral; Preserved; RNA-sequencing; T3; Terminal maturation.

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Conflict of interest statement

The authors have declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
Volcano plot of differentially expressed genes after T3 stimulation. Circles represent all expressed genes in OA explant cartilage with genes significantly differentially expressed after T3-induced hypertrophy indicated in red (up) or green (down) with an FDR > 0.05. X-axis represents fold change (FC) of gene expression in T3-treated compared to control cartilage
Fig. 2
Fig. 2
Gene expression in control and T3 stimulated explant cartilage, figure shows connected paired samples. VST data from RNA-seq analysis (paired samples from n = 8 donors). Statistical difference determined by DESeq analysis and with application of false discovery rate (FDR) correction. Validation data shown as -ΔCT values obtained by RT-qPCR analysis (paired samples from 8 donors). Statistical difference reflects linear generalized estimation equation (GEE). ** < 0.01;**** < 0.0001; n.s = not significant
Fig. 3
Fig. 3
Genes present in the top 25 pathways enriched in the GO biological process subontology. Only genes present in at least 3 pathways are shown. Color reflects fold change T3 compared to control
Fig. 4
Fig. 4
Illustrating the number of overlapping genes between T3 cartilage RNA-seq dataset, Karlsson OAH dataset [20], and RAAK OAP dataset [16]
See this image and copyright information in PMC

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