OP0369 Osteoarthritis-Driven Inflammatory Imprinting of Synovial Fibroblasts contributes to Gout Exacerbation through m6A modification of S100A4
Notice bibliographique
Résumé
Background: Osteoarthritis (OA) has been postulated as a significant intra-articular risk factor for the future development of gout; however, the causal link between OA and the exacerbation of gout remains enigmatic. Synovial fibroblasts (SFs) have been reported to acquire a memory-like phenotype under chronic inflammatory conditions to mediate arthritis remission, flare, and recurrence. Objectives: This study was undertaken to examine whether SF could be imprinted in the setting of OA, contributes to the development of gout. Methods: Human SFs were collected from osteoarthritic and normal joints and then treated with monosodium urate (MSU). Phenotypic modifications were examined to assess their association with the inflammatory response to MSU crystals and their potential role in accelerating the crystallization process. Epigenetic and transcriptomic alterations in SFs were identified. Mice with or without synovial macrophage depletion were subjected to destabilization of the medial meniscus (DMM) surgery and injected with MSU to confirm the mechanisms in vivo. Results: We demonstrated that upon in vitro stimulation with MSU crystals, SFs derived from patients with OA exhibited enhanced ability to activate the NLRP3 inflammasome and NF-kB, produce inflammatory mediators, and traffic and initialize macrophages and neutrophils via secreting chemokines (e.g., C–C motif chemokine ligand 2 and C–X–C motif chemokine ligand 2), as well as secrete excessive extracellular matrix, including collagen fibers promoting MSU crystallization. Collectively, these effects may contribute to development of the gout. Notably, this pathology was found to be dependent on METTL3/YTHDF2-mediated m6A demethylation of fibroblast specific protein 1 (FSP1)/S100A4. Moreover, we found that the previous subjection to destabilization of the medial meniscus (DMM) surgery rendered mice to develop more severe joint inflammation upon subsequent exposure to MSU crystals, which was independent of synovial macrophages. Finally, local targeting METTL3/S100A4 obviously abolished MSU crystal-induced joint inflammation secondary to OA settings in murine models. Conclusion: These findings demonstrate that m6A modification-mediated inflammatory imprinting of SFs in the setting of OA promotes an aggregated inflammatory response to MSU crystals, highlighting novel cellular-level and molecular targets to prevent the development of gout. REFERENCES: [1] Dalbeth N, Gosling AL, Gaffo A, et al. Gout. Lancet 2021;397:1843–55. DOI: 10.1016/S0140-6736(21)00569-9. [2] Dalbeth N, Stamp L. Hyperuricaemia and gout: time for a new staging system? Ann Rheum Dis 2014;73:1598–600. DOI: 10.1136/annrheumdis-2014-205304. [3] Dalbeth N, Phipps-Green A, Frampton C, et al. Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis. Ann Rheum Dis 2018;77:1048–52. DOI: 10.1136/annrheumdis-2017-212288. [4] McGill NW, Dieppe PA. Evidence for a promoter of urate crystal formation in gouty synovial fluid. Ann Rheum Dis 1991;50:558–61. DOI: 10.1136/ard.50.8.558. [5] Xu H, Qin H, Hua Y, et al. Contributions of joint damage-related events to gout pathogenesis: new insights from laboratory research. Ann Rheum Dis 2023;82:1511–5. DOI: 10.1136/ard-2023-224679. [6] Roddy E, Zhang W, Doherty M. Are joints affected by gout also affected by osteoarthritis? Ann Rheum Dis 2007;66:1374–7. DOI: 10.1136/ard.2006.063768. [7] Yokose C, Chen M, Berhanu A, et al. Gout and osteoarthritis: associations, pathophysiology, and therapeutic implications. Curr Rheumatol Rep 2016;18:65. DOI: 10.1007/s11926-016-0613-9. [8] Chhana A, Pool B, Wei Y, et al. Human cartilage homogenates influence the crystallization of monosodium urate and inflammatory response to monosodium urate crystals: A potential link between osteoarthritis and gout. Arthritis Rheumatol 2019;71:2090–9. DOI: 10.1002/art.41038. [9] Xu H, Zhang B, Chen Y, et al. Type II collagen facilitates gouty arthritis by regulating MSU crystallisation and inflammatory cell recruitment. Ann Rheum Dis 2023;82:416–27. DOI: 10.1136/ard-2022-222764. [10] Naik S, Fuchs E. Inflammatory memory and tissue adaptation in sickness and in health. Nature 2022;607:249–55. DOI: 10.1038/s41586-022-04919-3. Acknowledgements: NIL . Disclosure of Interests: None declared . © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».