{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:58:42Z","timestamp":1790791122145,"version":"4.1.0"},"reference-count":9,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pain is the defining symptom of knee osteoarthritis (OA), yet its molecular correlates in synovial tissue remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2009=\u200910; high vs low pain), characterized its pathway enrichment, tested specificity against an OA-versus-healthy contrast (GSE89408, n\u2009=\u200950), related it to inflammatory and fibrotic axes (GSE283079, n\u2009=\u200936 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\u2013Lane) from models adjusting for age and region cellularity, alongside correlation-aware competitive testing (CAMERA). This analysis plan was specified post hoc.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Discovery yielded an exploratory program of 38 genes (35 up-regulated). An epithelial\u2013mesenchymal transition (EMT)-like stromal\/remodeling signature \u2014 interpreted in synovium as matrix remodeling rather than literal epithelial transition \u2014 was the only Hallmark set of 50 significantly enriched (NES\u2009=\u20091.885, p\n                      <jats:sub>adj<\/jats:sub>\n                      \u2009=\u20090.0022), although at n\u2009=\u200910 it did not survive exact phenotype-label permutation (p\u2009=\u20090.226). 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\u2009=\u20090.010 and 0.005 at \u22655% and \u226510% detection across the discovery-derived hypotheses\u2009\u00d7\u2009compartments), persisting after adjustment for age and cellularity and against gene sets matched on abundance and detection, and carried by matrix, adhesion and TGF-\u03b2-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 \u22120.06 to +0.65); an undirected scan of all 50 Hallmark sets across three compartments yielded no set surviving correction (EMT q\u2009=\u20090.105); and a within-patient contrast did not confirm that the association differs between compartments (p\u2009=\u20090.196). 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0346948","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:33:44Z","timestamp":1790789624000},"page":"e0346948","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["An epithelial\u2013mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6851-6204","authenticated-orcid":true,"given":"Diovanni de Paula","family":"Ferreira","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias M\u00e9dicas, Universidade de Bras\u00edlia","place":["Bras\u00edlia, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7290-5824","authenticated-orcid":true,"given":"Rafael de Negreiros","family":"Botan","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias M\u00e9dicas, Universidade de Bras\u00edlia","place":["Bras\u00edlia, Brazil"]},{"name":"UnB","place":["Bras\u00edlia, Brazil"],"department":["Department of Oncology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wagner R.","family":"Martins","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias M\u00e9dicas, Universidade de Bras\u00edlia","place":["Bras\u00edlia, Brazil"]},{"name":"UnB","place":["Bras\u00edlia, Brazil"],"department":["Faculdade de Educa\u00e7\u00e3o F\u00edsica e Fisioterapia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iruena M.","family":"Kessler","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias M\u00e9dicas, Universidade de Bras\u00edlia","place":["Bras\u00edlia, Brazil"]},{"name":"UnB","place":["Bras\u00edlia, Brazil"],"department":["Department of Neurosurgery"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"issue":"6","key":"pone.0346948.ref001","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/art.43086","article-title":"Revisiting the synovium as a structural correlate of pain in osteoarthritis","volume":"77","author":"RE Miller","year":"2025","journal-title":"Arthritis Rheumatol"},{"issue":"7","key":"pone.0346948.ref002","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3390\/genes9070338","article-title":"Pain-associated transcriptome changes in synovium of knee osteoarthritis patients","volume":"9","author":"A Bratus-Neuenschwander","year":"2018","journal-title":"Genes (Basel)"},{"key":"pone.0346948.ref003","doi-asserted-by":"crossref","first-page":"103618","DOI":"10.1016\/j.ebiom.2021.103618","article-title":"Synovial tissue from sites of joint pain in knee osteoarthritis patients exhibits a differential phenotype with distinct fibroblast subsets","volume":"72","author":"DE Nanus","year":"2021","journal-title":"EBioMedicine"},{"issue":"7760","key":"pone.0346948.ref004","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41586-019-1263-7","article-title":"Distinct fibroblast subsets drive inflammation and damage in arthritis","volume":"570","author":"AP Croft","year":"2019","journal-title":"Nature"},{"issue":"12","key":"pone.0346948.ref005","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"issue":"12","key":"pone.0346948.ref006","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1093\/bioinformatics\/bty895","article-title":"Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences","volume":"35","author":"A Zhu","year":"2019","journal-title":"Bioinformatics"},{"key":"pone.0346948.ref007","article-title":"Fast gene set enrichment analysis","author":"G Korotkevich","year":"2019","journal-title":"bioRxiv"},{"issue":"2","key":"pone.0346948.ref008","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.183690","article-title":"CD34hi subset of synovial fibroblasts contributes to fibrotic phenotype of human knee osteoarthritis","volume":"10","author":"J Miyahara","year":"2025","journal-title":"JCI Insight"},{"issue":"6","key":"pone.0346948.ref009","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1002\/art.43089","article-title":"Association of synovial innate immune exhaustion with worse pain in knee osteoarthritis","volume":"77","author":"HT Philpott","year":"2025","journal-title":"Arthritis Rheumatol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0346948","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:33:47Z","timestamp":1790789627000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0346948"}},"subtitle":[],"editor":[{"given":"Rongchun","family":"Han","sequence":"first","affiliation":[{"name":"Anhui University of Chinese Medicine","place":["CHINA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":9,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0346948","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]}}}