{ "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.", "abstract_shown": true, "affiliations": [ "Programa de Pós-Graduação em Ciências Médicas, Universidade de Brasília, Brasília, Brazil", "Department of Oncology, UnB, Brasília, Brazil", "Faculdade de Educação Física e Fisioterapia, UnB, Brasília, Brazil", "Department of Neurosurgery, UnB, Brasília, Brazil" ], "article_type": "Research Article", "arxiv": null, "author_total": 4, "authors": [ { "affs": [ 0 ], "name": "Diovanni de Paula Ferreira" }, { "affs": [ 1 ], "name": "Rafael de Negreiros Botan" }, { "affs": [ 2 ], "name": "Wagner R. Martins" }, { "affs": [ 3 ], "name": "Iruena M. Kessler" } ], "bibtex": "https://research.draconitic.com/paper/f9zv4y83vrjmp.bib", "cited_by": 0, "doi": "10.1371/journal.pone.0346948", "fulltext_url": null, "id": "f9zv4y83vrjmp", "issns": [ "1932-6203" ], "landing_url": "https://doi.org/10.1371/journal.pone.0346948", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2745|Osteoarthritis Treatment and Mechanisms" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Connective tissue/Connective tissue cells/Fibroblasts" ], [ "plos", "/Biology and life sciences/Anatomy/Body limbs/Legs/Knees" ], [ "plos", "/Biology and life sciences/Anatomy/Musculoskeletal system/Skeleton/Skeletal joints/Knees" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Connective tissue cells/Fibroblasts" ], [ "plos", "/Biology and life sciences/Computational biology/Genome analysis/Transcriptome analysis" ], [ "plos", "/Biology and life sciences/Genetics/Genomics/Genome analysis/Transcriptome analysis" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Computer and information sciences/Geoinformatics/Spatial analysis" ], [ "plos", "/Earth sciences/Geography/Geoinformatics/Spatial analysis" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Connective tissue/Connective tissue cells/Fibroblasts" ], [ "plos", "/Medicine and health sciences/Anatomy/Body limbs/Legs/Knees" ], [ "plos", "/Medicine and health sciences/Anatomy/Musculoskeletal system/Skeleton/Skeletal joints/Knees" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Pain" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Medicine and health sciences/Rheumatology/Arthritis/Osteoarthritis" ], [ "plos", "/Physical sciences/Mathematics/Discrete mathematics/Combinatorics/Permutation" ] ], "openalex": "W7214920803", "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0346948&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-30", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/f9zv4y83vrjmp.ris", "sources": [ { "first_seen": "2026-10-30T12:17:37Z", "native_id": "10.1371/journal.pone.0346948", "source": "plos", "url": "https://doi.org/10.1371/journal.pone.0346948" } ], "subjects": [ { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "An epithelial–mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis", "title_text": "An epithelial–mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:37Z", "url": "https://research.draconitic.com/paper/f9zv4y83vrjmp", "venue": "PLOS One", "versions": [] }