Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis

Journal name:
Nature Reviews Rheumatology
Year published:
Published online


Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. Furthermore, we now appreciate that OA pathogenesis involves not only breakdown of cartilage, but also remodelling of the underlying bone, formation of ectopic bone, hypertrophy of the joint capsule, and inflammation of the synovial lining. That is, OA is a disorder of the joint as a whole, with inflammation driving many pathologic changes. The inflammation in OA is distinct from that in rheumatoid arthritis and other autoimmune diseases: it is chronic, comparatively low-grade, and mediated primarily by the innate immune system. Current treatments for OA only control the symptoms, and none has been FDA-approved for the prevention or slowing of disease progression. However, increasing insight into the inflammatory underpinnings of OA holds promise for the development of new, disease-modifying therapies. Indeed, several anti-inflammatory therapies have shown promise in animal models of OA. Further work is needed to identify effective inhibitors of the low-grade inflammation in OA, and to determine whether therapies that target this inflammation can prevent or slow the development and progression of the disease.

At a glance


  1. Radiographic and histologic findings in OA: evidence of inflammation and bone remodelling.
    Figure 1: Radiographic and histologic findings in OA: evidence of inflammation and bone remodelling.

    a | Gadolinium-enhanced MRI (sagittal view) scan of a knee with multiple features typical of OA: synovial inflammation, cartilage degradation, and bone remodelling. Short white arrows indicate marked peripatellar synovitis, dashed white arrows indicate bone marrow lesions, and the long white arrow pointing to bright white structures indicates bone cysts. b | A synovial biopsy specimen obtained during meniscectomy from a patient with knee OA, showing histological evidence of inflammation. Arrows indicate the presence of perivascular mononuclear cell accumulation. Original magnification × 5, haematoxylin and eosin stain. c | Remodelling of the subchondral bone in OA, as detected by radiography of the knee of an individual with OA (left), and by gross examination of distal femurs of a dog (right) that had undergone unilateral anterior cruciate ligament transection. In the destabilized dog knee, full-thickness ulceration of the articular cartilage has developed on the medial femoral condyle, and striking remodelling of the subchondral bone has occurred, with enlargement of the medial femoral condyle. The articular cartilage and bone on the contralateral dog knee appear grossly normal. d | Microfractures and microcracks in subchondral bone of an individual with OA. Part a adapted from Felson, D. T. Developments in the clinical understanding of osteoarthritis. Arthritis Res. Ther. 11, 203 (2009)168. The original article is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Part b reproduced from Scanzello, C. R. et al. Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms. Arthritis Rheum. 63, 391400 (2011)26. Parts c, d reproduced from Brandt, K. D., Dieppe, P. & Radin, E. L. Commentary: is it useful to subset “primary” osteoarthritis? A critique based on evidence regarding the etiopathogenesis of osteoarthritis. Semin. Arthritis Rheum. 39, 8195 (2009)11.

  2. The pathobiology of OA.
    Figure 2: The pathobiology of OA.

    Comparison of the normal joint (left side) and the OA joint (right side), demonstrating that OA is a disease that affects the entire joint structure, including the articular cartilage, synovium, subchondral bone, joint capsule, and other components of the joint.

  3. The molecular mechanisms of low-grade inflammation in OA.
    Figure 3: The molecular mechanisms of low-grade inflammation in OA.

    Several inflammatory pathways and mechanisms are likely to contribute to the pathogenesis of OA. In this paradigm, injury or overuse, often in the context of other risk factors, triggers a vicious cycle of local tissue damage, failed tissue repair, and low-grade inflammation involving a number of molecular components and mechanisms in the joint. This low-grade inflammation contributes to or mediates progressive cartilage loss, pain, and joint dysfunction. CPB, carboxypeptidase B; DAMPs, disease-associated molecular patterns; NO, nitric oxide.

  4. Targeting low-grade inflammation in OA.
    Figure 4: Targeting low-grade inflammation in OA.

    Can abrogating low-grade inflammatory responses break the feed-forward cycle of joint damage and breakdown leading to inflammation that promotes the pathogenesis of OA? Examples of risk factors for OA, cell types involved in its pathogenesis, and molecular components in the inflammatory pathways that are potential therapeutic targets for preventing or treating OA are shown. CPB, carboxypeptidase B; DAMPs, disease-associated molecular patterns; NO, nitric oxide; OA, osteoarthritis.


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  1. Geriatric Research Education and Clinical Centers, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USA.

    • William H. Robinson,
    • Christin M. Lepus,
    • Qian Wang,
    • Harini Raghu,
    • Rong Mao,
    • Tamsin M. Lindstrom &
    • Jeremy Sokolove
  2. Division of Immunology and Rheumatology, Stanford University School of Medicine, Center for Clinical Sciences Research (CCSR) 4135, 269 Campus Drive, Stanford, California 94305, USA.

    • William H. Robinson,
    • Christin M. Lepus,
    • Qian Wang,
    • Harini Raghu,
    • Rong Mao,
    • Tamsin M. Lindstrom &
    • Jeremy Sokolove


W.H.R. and R.M. wrote the article. All authors researched the data for the article, contributed substantially to discussions of its content, and participated in review and/or editing of the manuscript before submission.

Competing interests statement

J.S. is an employee of AbbVie. All other authors declare no competing interests.

Corresponding author

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Author details

  • William H. Robinson

    William H. Robinson received his MD and PhD from Stanford University (USA) and completed his residency training in Internal Medicine at the University of California San Francisco (USA). His laboratory pioneered high-throughput approaches to characterize antibody repertoires, and is leading efforts to define the mechanistic role of citrullination in rheumatoid arthritis and of low-grade inflammation in osteoarthritis. He holds a joint appointment as an Associate Professor of Medicine at Stanford University School of Medicine and as a Staff Physician at the Department of Veterans Affairs Palo Alto Health Care System (USA).

  • Christin M. Lepus

    Christin M. Lepus received her BA in Biology from Washington University in St Louis (USA). She is currently an MD/PhD student in the Medical Scientist Training Program at Stanford University School of Medicine (USA). She is conducting her PhD research in immunology in the Robinson Laboratory, where she investigates the role of innate immune mechanisms in osteoarthritis.

  • Qian Wang

    Qian Wang received her MD from the Shandong University (China) and her PhD degree from the Chinese Academy of Medical Sciences (China). She completed her Postdoctoral Fellowship at Stanford University (USA), where she is currently a Research Associate in the Robinson Laboratory.

  • Harini Raghu

    Harini Raghu received her BSc in Biotechnology from Bangalore University (India) and her MSc in Biotechnology from VIT University (India). She completed her PhD at the University of Cincinnati School of Medicine (USA). She is currently a postdoctoral fellow in the Robinson Laboratory at Stanford University School of Medicine (USA).

  • Rong Mao

    Rong Mao received her BA in Biochemical Sciences from Harvard University (USA) and her PhD in Biochemistry, Cellular and Molecular Biology from Johns Hopkins University School of Medicine (USA). She completed her postdoctoral training at Massachusetts Institute of Technology and Stanford University (USA). She is currently an investigator in the Robinson Laboratory at Stanford University School of Medicine (USA).

  • Tamsin M. Lindstrom

    Tamsin M. Lindstrom completed a BSc in Biology at the University of Nottingham (UK), and a PhD in Reproductive Sciences at Imperial College London (UK). She spent a year at GlaxoSmithKline (UK), in the Departments of Virology and Respiratory Disease. Dr Lindstrom was a Research Associate in the Robinson laboratory at Stanford University School of Medicine (USA).

  • Jeremy Sokolove

    Jeremy Sokolove received his undergraduate degree from the University of New Hampshire and his medical degree from Boston University Medical Center (USA), where he subsequently completed his medical residency and served as chief medical resident. He completed a Rheumatology Fellowship and postdoctoral training in immunology in the Robinson Laboratory at Stanford University (USA). Before joining AbbVie Pharmaceutical (USA) in 2016, he was an Adjunct Assistant Professor at Stanford University and led a research group at the Veterans Affairs Palo Alto Health Care System (USA) studying the role of protein citrullination and links between innate and adaptive immunity in rheumatoid arthritis.

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