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  • Review Article
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Failure of cartilage regeneration: emerging hypotheses and related therapeutic strategies

Nature Reviews Rheumatology volume 19, pages 403–416 (2023)Cite this article

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Abstract

Osteoarthritis (OA) is a disabling condition that affects billions of people worldwide and places a considerable burden on patients and on society owing to its prevalence and economic cost. As cartilage injuries are generally associated with the progressive onset of OA, robustly effective approaches for cartilage regeneration are necessary. Despite extensive research, technical development and clinical experimentation, no current surgery-based, material-based, cell-based or drug-based treatment can reliably restore the structure and function of hyaline cartilage. This paucity of effective treatment is partly caused by a lack of fundamental understanding of why articular cartilage fails to spontaneously regenerate. Thus, research studies that investigate the mechanisms behind the cartilage regeneration processes and the failure of these processes are critical to instruct decisions about patient treatment or to support the development of next-generation therapies for cartilage repair and OA prevention. This Review provides a synoptic and structured analysis of the current hypotheses about failure in cartilage regeneration, and the accompanying therapeutic strategies to overcome these hurdles, including some current or potential approaches to OA therapy.

Key points

  • Multiple pathways can cause cartilage regeneration to fail following injury, thereby leading to a cascade of events that ultimately results in a degenerative disease state.

  • Various hypotheses for why cartilage regeneration fails exist relating to a lack of regeneration-competent cells, pathological mechanical changes, non-resolving inflammation and metabolic switches.

  • Treatment strategies should not only consider the potential mechanisms underlying the initial failure in cartilage regeneration but also the stage of disease progression.

  • The cause of entry into the cascade of events that prevent cartilage regeneration might not necessarily be the target point of exit of an ideal treatment strategy.

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Fig. 1: Postulated mechanisms of cellular-based strategies for cartilage regeneration.
Fig. 2: Postulated mechanisms of abnormal joint loading aggravating cartilage damage following injury.
Fig. 3: Inflammatory events involved in cartilage regeneration and associated therapeutic strategies.
Fig. 4: Strategies for targeting the metabolic changes that negatively affect cartilage regeneration.
Fig. 5: Clinical stage of strategies targeting various hypotheses for why cartilage regeneration fails.
Fig. 6: Potential entry points and exit strategies relating to cartilage regeneration failure.

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Acknowledgements

The idea for this Review was developed during a Travelling Fellowship sponsored by the ON Foundation and the International Cartilage Regeneration & Joint Preservation Society (ICRS). The authors would like to extend their thanks to these organizations for the opportunity. The authors would also like to thank the following individuals, who hosted the Fellows during the Fellowship and inspired this piece of work: Georg Duda, Laura di Girolamo, Kay Horsch, Elizaveta Kon, Jos Malda, Sylvia Nürnberger, Peter Angele, Girish Pattapa, Heinz Redl, Matthias Steinwachs, Bill Taylor, Siegfried Trattnig and Marcy Wong.

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Authors and Affiliations

  1. Orthopaedic Research Group, Coimbatore, Tamil Nadu, India

    Sathish Muthu

  2. Department of Biotechnology, School of Engineering and Technology, Sharda University, New Delhi, India

    Sathish Muthu

  3. Department of Biotechnology, Faculty of Engineering, Karpagam Academy of Higher Education, Coimbatore, India

    Sathish Muthu

  4. Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA

    Jasmijn V. Korpershoek

  5. Department of Orthopedics, University Medical Center Utrecht, Utrecht, Netherlands

    Jasmijn V. Korpershoek

  6. Unidade Local de Saúde do Litoral Alentejano, Orthopedic Department, Santiago do Cacém, Portugal

    Emanuel J. Novais

  7. Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    Emanuel J. Novais

  8. Division of Cell Matrix Biology & Regenerative Medicine, University of Manchester, Manchester, UK

    Gwenllian F. Tawy

  9. Institute of Lifecourse and Medical Sciences, University of Liverpool, Liverpool, UK

    Anthony P. Hollander

  10. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland

    Ivan Martin

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Contributions

S.M., J.V.K., E.J.N. and G.F.T. researched data for the article. I.M., S.M., J.V.K., E.J.N. and G.F.T. wrote the article. All the authors contributed substantially to the discussion of content and reviewed and/or edited the manuscript before submission.

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Nature Reviews Rheumatology thanks D. Grande, C. Evans, J. Elisseeff and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Muthu, S., Korpershoek, J.V., Novais, E.J. et al. Failure of cartilage regeneration: emerging hypotheses and related therapeutic strategies. Nat Rev Rheumatol 19, 403–416 (2023). https://doi.org/10.1038/s41584-023-00979-5

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