An epithelial–mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis

Diovanni de Paula Ferreira , Rafael de Negreiros Botan, Wagner R. Martins, Iruena M. Kessler

Abstract

Pain is the defining symptom of knee osteoarthritis (OA), yet its molecular correlates in synovial tissue remain incompletely understood.

Introduction

Pain is the defining symptom of knee osteoarthritis (OA), yet its molecular basis in synovial tissue remains poorly understood. Clinical pain severity in OA correlates imperfectly with structural damage, and synovial inflammation and remodeling are increasingly recognized as pain-relevant features beyond cartilage-centric pathology [1].

Methods

The discovery analyses were specified before the spatial cohort was examined. The spatial analysis plan reported here — detection filtering, covariate adjustment, permutation scheme and multiplicity strategy — was specified post hoc, after earlier analyses of the same cohort had been performed.

Results

Differential expression of high- versus low-pain synovium (GSE99662) yielded 38 genes (35 up-regulated, 3 down-regulated) at FDR < 0.10 and |log 2 FC| > 0.5 (Fig 1; sensitivity to alternative thresholds in S2 Table).

Discussion

We describe an exploratory transcriptomic program associated with pain severity in knee-OA synovium whose dominant signal is an EMT-like stromal/remodeling signature, and we examine whether it is recoverable in a larger, independent, patient-level spatial cohort.

Citation: Ferreira DdP, Botan RdN, Martins WR, Kessler IM (2026) An epithelial–mesenchymal transition-like synovial stromal-remodeling programme associated with knee osteoarthritis pain: Exploratory transcriptomic discovery and spatial analysis. PLoS One 21(9): e0346948. https://doi.org/10.1371/journal.pone.0346948

Editor: Rongchun Han, Anhui University of Chinese Medicine, CHINA

Received: March 23, 2026; Accepted: September 15, 2026; Published: September 30, 2026

Copyright: © 2026 Ferreira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data underlying the findings are fully available without restriction. No primary data were generated by this study; all analyses used existing, publicly available datasets from the NCBI Gene Expression Omnibus (GEO) repository, accessible at https://www.ncbi.nlm.nih.gov/geo/ under accession numbers GSE99662, GSE89408, GSE283079, GSE248454, GSE157364, GSE176308, and GSE176223. The complete annotated analysis code is publicly available in the GitHub repository RafaelBotan/knee-oa-synovial-pain-omics (https://github.com/RafaelBotan/knee-oa-synovial-pain-omics) and is permanently archived on Zenodo at https://doi.org/10.5281/zenodo.21741007 (DOI: https://doi.org/10.5281/zenodo.21741007, release v2.0.0), which contains the analyses reported in this revision together with the log of each run; the concept DOI https://doi.org/10.5281/zenodo.21739159 always resolves to the most recent version.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.