EZH2 coordinates inflammatory and pain-associated pathways across joint compartments in osteoarthritis.

@article{brochard2026ezh2,
  title = {{EZH2 coordinates inflammatory and pain-associated pathways across joint compartments in osteoarthritis.}},
  author = {Sybille Brochard and Alison Vanlaeys and Mahdia Taieb and Isabelle Richard and Juliette Aury-Landas and Benoit Bernay and Julien Pontin and Celia Seillier and Nina Bon and Baptiste Picart and Claire Pecqueur and Olivier Toutirais and Claire Vinatier and Jérôme Guicheux and Eric Maubert and Véronique Agin and Karim Boumediene and Catherine Bauge},
  journal = {Molecular biomedicine},
  year = {2026},
  month = oct,
  doi = {10.1186/s43556-026-00643-w},
  url = {https://europepmc.org/article/MED/42920051},
  note = {CC BY},
}

TY  - JOUR
TI  - EZH2 coordinates inflammatory and pain-associated pathways across joint compartments in osteoarthritis.
AU  - Sybille Brochard
AU  - Alison Vanlaeys
AU  - Mahdia Taieb
AU  - Isabelle Richard
AU  - Juliette Aury-Landas
AU  - Benoit Bernay
AU  - Julien Pontin
AU  - Celia Seillier
AU  - Nina Bon
AU  - Baptiste Picart
AU  - Claire Pecqueur
AU  - Olivier Toutirais
AU  - Claire Vinatier
AU  - Jérôme Guicheux
AU  - Eric Maubert
AU  - Véronique Agin
AU  - Karim Boumediene
AU  - Catherine Bauge
PY  - 2026
DA  - 2026/10/24
JO  - Molecular biomedicine
DO  - 10.1186/s43556-026-00643-w
UR  - https://europepmc.org/article/MED/42920051
AB  - Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for H3K27 trimethylation, has emerged as a potential therapeutic target in osteoarthritis (OA). However, its contribution to the multicellular mechanisms driving joint degeneration and pain remains poorly understood. Here, we investigated the effects of pharmacological EZH2 inhibition in a pain-relevant murine OA model and explored its cellular and molecular consequences across OA-associated cell populations. OA was induced in mice by intra-articular monosodium iodoacetate (MIA) injection followed by local administration of the EZH2 inhibitor EPZ-6438. Joint pathology and pain-related behaviors were assessed by histological and functional analyses. Mechanistic studies were performed in primary human OA fibroblast-like synoviocytes and bone marrow-derived cells using targeted gene expression analyses, proteomics and ChIP-seq approaches. EZH2 inhibition reduced cartilage damage, synovial inflammation and pain-related behavioral alterations in vivo. In OA synoviocytes, EPZ-6438 decreased the expression of inflammatory, catabolic and pain-associated mediators while promoting autophagy-related responses. Proteomic and ChIP-seq analyses revealed EZH2-dependent regulation of inflammatory pathways, cellular homeostasis and neuronal-associated processes, including axon guidance-related pathways. ChIP-seq further identified inflammation-dependent EZH2 recruitment to promoters of neurodevelopmental regulators, including PAX6, suggesting a potential contribution of EZH2 to neuronal-associated mechanisms in OA. In addition, EZH2 inhibition reduced macrophage inflammatory activation and osteoclast differentiation. Together, these findings identify EZH2 as a candidate epigenetic regulator linking inflammatory, neuroimmune and osteoimmune pathways across the osteoarthritic joint. Targeting EZH2 may represent a therapeutic strategy to simultaneously modulate joint inflammation, remodeling and pain-associated pathways.
SN  - 2662-8651
ER  -