OP0369 Osteoarthritis-Driven Inflammatory Imprinting of Synovial Fibroblasts contributes to Gout Exacerbation through m6A modification of S100A4
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".