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The role of the immune system in osteoarthritis: mechanisms, challenges and future directions

Nature Reviews Rheumatology volume 21, pages 221–236 (2025)Cite this article

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Abstract

Osteoarthritis (OA) is a chronic joint disease that has long been considered a simple wear-and-tear condition. Over the past decade, research has revealed that various inflammatory features of OA, such as low-grade peripheral inflammation and synovitis, contribute substantially to the pathophysiology of the disease. Technological advances in the past 5 years have revealed a large diversity of innate and adaptive immune cells in the joints, particularly in the synovium and infrapatellar fat pad. Notably, the presence of synovial lymphoid structures, circulating autoantibodies and alterations in memory T cell and B cell populations have been documented in OA. These data indicate a potential contribution of self-reactivity to the disease pathogenesis, blurring the often narrow and inaccurate line between chronic inflammatory and autoimmune diseases. The diverse immune changes associated with OA pathogenesis can vary across disease phenotypes, and a better characterization of their underlying molecular endotypes will be key to stratifying patients, designing novel therapeutic approaches and ultimately ameliorating treatment allocation. Furthermore, examining both articular and systemic alterations, including changes in the gut–joint axis and microbial dysbiosis, could open up novel avenues for OA management.

Key points

  • Technological advances, such as single-cell RNA sequencing, have revealed an unexpected diversity of immune cells within joint tissues in osteoarthritis (OA), particularly in the synovium and infrapatellar fat pad.

  • At advanced stages of OA, aggregates that comprise B cells and T cells surrounded by plasma cells are observed in synovial tissues.

  • The presence of circulating autoantibodies and alterations in memory T cell and B cell populations that are reported in OA indicate a potential contribution of self-reactivity to disease pathogenesis.

  • Immune changes in OA contribute to both articular and systemic low-grade inflammation, the underlying mechanisms of which might vary depending on the OA phenotype, representing potential clinically relevant therapeutic targets.

  • The gut microbiota and associated immune responses have a role in OA pathophysiology, and potentially represent novel therapeutic targets.

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Fig. 1: Immune cells in the synovium and infrapatellar fat pad in health and osteoarthritis.
Fig. 2: The influence of the immune system on the joint and the periphery in osteoarthritis.
Fig. 3: Towards personalized medicine in osteoarthritis.

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Acknowledgements

We particularly would like to thank A. Cardon and C. Morizot for their involvement in the preparation of the Review outline and for sharing their suggestions related to the preparation of this manuscript. We would also like to thank the following funding sources for their support: Fondation pour la recherche médicale (grant number ARF202004011786 to M.-A.B.; EQU202303016276 to J.G. and M.-A.B. and PFG-P 2022 to J.G.), Inserm (ATIP-Avenir program to M.-A.B.), Region Grand Est (FRCR TARGET to D.M.), Agence Nationale de la Recherche (ANR-18-CE18-0010 PPAROA to J.G., ANR-23-CE18-0018 TrypENGINE to D.M.), Fondation Arthritis (Projet labellisé TRYPTHERA to D.M.; and Projet émergent SPOTT to M.-A.B.), Going Inside Osteoarthritis-Related Pain Phenotyping (GO-PAIN) ERA-NET NEURON grant (to J.S.) and Pfizer ADVANCE 2020 grant (to J.S. and F.B.).

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Authors and Affiliations

  1. Université de Lorraine, CNRS, IMoPA, Nancy, France

    David Moulin

  2. CHRU-Nancy, IHU INFINY, Nancy, France

    David Moulin

  3. Department of Rheumatology, Saint-Antoine Hospital, Centre de Recherche Saint-Antoine, Inserm, Sorbonne Université UMRS 938, Assistance Publique-Hôpitaux de Paris, Paris, France

    Jérémie Sellam & Francis Berenbaum

  4. Nantes Université, Oniris, INSERM, CHU Nantes, UMR1229 Regenerative Medicine and Skeleton, RMeS, Nantes, France

    Jérôme Guicheux & Marie-Astrid Boutet

  5. Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK

    Marie-Astrid Boutet

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Contributions

M.-A.B., D.M., J.G., J.S., and F.B. researched data for the article and wrote the article. All authors contributed substantially to discussion of the content and/or edited the manuscript before submission.

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Correspondence to David Moulin or Marie-Astrid Boutet.

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Competing interests

F.B. received an institutional grant from TRB Chemedica and Pfizer and consulting fees from AstraZeneca, Boehringer Ingelheim, Bone Therapeutics, Cellprothera, Galapagos, Gilead, Grunenthal, GSK, Lilly, MerckSerono, MSD, Nordic Bioscience, Novartis, Pfizer, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, 4 P Pharma and 4Moving Biotech. J.S. reports personal fees from MSD, Pfizer, AbbVie, Fresenius Kabi, BMS, Lilly, Novartis, Galapagos, AstraZeneca, UCB, Grunenthal and Janssen and research grants from Pfizer and Schwa Medico. J.G. received consulting fees from BMS, Graftys, PKmed, HTL biotechnology, Cellprothera, GSK, Peptinov and CEVA.

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Nature Reviews Rheumatology thanks Mary Goldring; Mohit Kapoor, who co-reviewed with Jason Rockel and Yusheng Li for their contribution to the peer review of this work.

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Review criteria

A search of PubMed for original relevant and high-quality articles published between 2005 and 2024 (a few older and original studies are also cited in the text where relevant) that focus on the diversity and role of innate and adaptive immune cells in OA. Search terms included “OSTEOARTHRITIS”, “IMMUNE CELLS”, “IMMUNITY”, “MICROBIOTA” and “TREATMENT”, alone and in combination. All articles identified were English-language, full-text papers. We also searched the reference lists of identified articles for additional relevant papers.

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Moulin, D., Sellam, J., Berenbaum, F. et al. The role of the immune system in osteoarthritis: mechanisms, challenges and future directions. Nat Rev Rheumatol 21, 221–236 (2025). https://doi.org/10.1038/s41584-025-01223-y

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