PloS one · 2026
An epithelial-mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis.
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Ferreira Diovanni de Paula, Botan Rafael de Negreiros, Martins Wagner R, Kessler Iruena M
Аннотация
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.
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.