An epithelial–mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis
4 affiliations
- 1Programa de Pós-Graduação em Ciências Médicas, Universidade de Brasília, Brasília, Brazil
- 2Department of Oncology, UnB, Brasília, Brazil
- 3Faculdade de Educação Física e Fisioterapia, UnB, Brasília, Brazil
- 4Department of Neurosurgery, UnB, Brasília, Brazil
Abstract
Background: Pain is the defining symptom of knee osteoarthritis (OA), yet its molecular correlates in synovial tissue remain incompletely understood. Methods: Across publicly available synovial transcriptomic datasets, we derived an exploratory pain-associated gene program by differential expression in synovium stratified by pain severity (GSE99662, n = 10; high vs low pain), characterized its pathway enrichment, tested specificity against an OA-versus-healthy contrast (GSE89408, n = 50), related it to inflammatory and fibrotic axes (GSE283079, n = 36 OA), and examined a larger, independent patient-level whole-transcriptome spatial cohort (Philpott et al. 2025 [1]; GSE248454; 32 knee-OA patients, 16 more- vs 16 less-pain; intimal-lining, sublining and perivascular compartments, one region per compartment per patient). The spatial analysis applied a limit-of-quantification detection filter and permutation of residuals (Freedman–Lane) from models adjusting for age and region cellularity, alongside correlation-aware competitive testing (CAMERA). This analysis plan was specified post hoc. Results: Discovery yielded an exploratory program of 38 genes (35 up-regulated). An epithelial–mesenchymal transition (EMT)-like stromal/remodeling signature — interpreted in synovium as matrix remodeling rather than literal epithelial transition — was the only Hallmark set of 50 significantly enriched (NES = 1.885, padj = 0.0022), although at n = 10 it did not survive exact phenotype-label permutation (p = 0.226). In the spatial cohort only 4,584 of 18,695 targets were above the detection limit in a typical region. After filtering, the discovery-derived Hallmark-EMT programme was positively associated with more pain in sublining regions (Holm-adjusted p = 0.010 and 0.005 at ≥5% and ≥10% detection across the discovery-derived hypotheses × compartments), persisting after adjustment for age and cellularity and against gene sets matched on abundance and detection, and carried by matrix, adhesion and TGF-β-associated transcripts. Three limits are reported with equal weight: the effect on the module scale was modest and imprecise (+0.30 z-units, 95% CI −0.06 to +0.65); an undirected scan of all 50 Hallmark sets across three compartments yielded no set surviving correction (EMT q = 0.105); and a within-patient contrast did not confirm that the association differs between compartments (p = 0.196). The 35-gene signature did not replicate in any compartment; a nominal unadjusted perivascular association did not survive adjustment, attenuated primarily by age. The programme was not enriched in OA-versus-healthy synovium. Conclusions: An EMT-like stromal-remodeling transcriptional programme is associated with worse patient-level knee pain in sublining synovium. The evidence is exploratory and method-dependent, the compartment difference is not established, and the specific discovery signature does not generalize.
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BibTeX
@article{ferreira2026epithelialmesenchymal,
title = {{An epithelial–mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis}},
author = {Diovanni de Paula Ferreira and Rafael de Negreiros Botan and Wagner R. Martins and Iruena M. Kessler},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0346948},
url = {https://doi.org/10.1371/journal.pone.0346948},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - An epithelial–mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis
AU - Diovanni de Paula Ferreira
AU - Rafael de Negreiros Botan
AU - Wagner R. Martins
AU - Iruena M. Kessler
PY - 2026
DA - 2026/09/30
JO - PLOS One
DO - 10.1371/journal.pone.0346948
UR - https://doi.org/10.1371/journal.pone.0346948
AB - Background: Pain is the defining symptom of knee osteoarthritis (OA), yet its molecular correlates in synovial tissue remain incompletely understood. Methods: Across publicly available synovial transcriptomic datasets, we derived an exploratory pain-associated gene program by differential expression in synovium stratified by pain severity (GSE99662, n = 10; high vs low pain), characterized its pathway enrichment, tested specificity against an OA-versus-healthy contrast (GSE89408, n = 50), related it to inflammatory and fibrotic axes (GSE283079, n = 36 OA), and examined a larger, independent patient-level whole-transcriptome spatial cohort (Philpott et al. 2025 [1]; GSE248454; 32 knee-OA patients, 16 more- vs 16 less-pain; intimal-lining, sublining and perivascular compartments, one region per compartment per patient). The spatial analysis applied a limit-of-quantification detection filter and permutation of residuals (Freedman–Lane) from models adjusting for age and region cellularity, alongside correlation-aware competitive testing (CAMERA). This analysis plan was specified post hoc. Results: Discovery yielded an exploratory program of 38 genes (35 up-regulated). An epithelial–mesenchymal transition (EMT)-like stromal/remodeling signature — interpreted in synovium as matrix remodeling rather than literal epithelial transition — was the only Hallmark set of 50 significantly enriched (NES = 1.885, padj = 0.0022), although at n = 10 it did not survive exact phenotype-label permutation (p = 0.226). In the spatial cohort only 4,584 of 18,695 targets were above the detection limit in a typical region. After filtering, the discovery-derived Hallmark-EMT programme was positively associated with more pain in sublining regions (Holm-adjusted p = 0.010 and 0.005 at ≥5% and ≥10% detection across the discovery-derived hypotheses × compartments), persisting after adjustment for age and cellularity and against gene sets matched on abundance and detection, and carried by matrix, adhesion and TGF-β-associated transcripts. Three limits are reported with equal weight: the effect on the module scale was modest and imprecise (+0.30 z-units, 95% CI −0.06 to +0.65); an undirected scan of all 50 Hallmark sets across three compartments yielded no set surviving correction (EMT q = 0.105); and a within-patient contrast did not confirm that the association differs between compartments (p = 0.196). The 35-gene signature did not replicate in any compartment; a nominal unadjusted perivascular association did not survive adjustment, attenuated primarily by age. The programme was not enriched in OA-versus-healthy synovium. Conclusions: An EMT-like stromal-remodeling transcriptional programme is associated with worse patient-level knee pain in sublining synovium. The evidence is exploratory and method-dependent, the compartment difference is not established, and the specific discovery signature does not generalize.
SN - 1932-6203
ER -