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Bone marrow lesions: plugging the holes in our knowledge using animal models

Nature Reviews Rheumatology volume 19, pages 429–445 (2023)Cite this article

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Abstract

Bone marrow lesions (BMLs), which are early signs of osteoarthritis (OA) that are associated with the presence, onset and severity of pain, represent an emerging imaging biomarker and clinical target. Little is known, however, regarding their early spatial and temporal development, structural relationships or aetiopathogenesis, because of the sparsity of human early OA imaging and paucity of relevant tissue samples. The use of animal models is a logical approach to fill the gaps in our knowledge, and it can be informed by appraising models in which BMLs and closely related subchondral cysts have already been reported, including in spontaneous OA and pain models. The utility of these models in OA research, their relevance to clinical BMLs and practical considerations for their optimal deployment can also inform medical and veterinary clinicians and researchers alike.

Key points

  • Bone marrow lesions (BMLs) are early signs of osteoarthritis (OA) that are associated with pain onset and severity, and they therefore represent potential biomarkers of OA and therapeutic targets.

  • Human studies of BMLs are limited by long imaging intervals and lack of joint tissue availability, particularly in early-stage OA or pre-OA, whereas animal studies have no such restrictions.

  • Available animal models exhibiting BMLs (or closely related subchondral cysts) include induced models (with induction by joint destabilization, loading or chemical treatment) and spontaneous models.

  • Animal BML models can represent both fast-onset traumatic and slower-onset ‘naturally occurring’ OA, and the occurrence of BMLs before and after cartilage lesion development.

  • Collectively, animal models provide opportunities for exploring BML aetiopathogenesis and bone–cartilage crosstalk, elucidating structural associations longitudinally and trialling therapeutic interventions before back-translating the results to humans.

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Fig. 1: The two main theories of subchondral cyst formation in truly subchondral regions.
Fig. 2: The vascular ageing theory of subchondral cyst formation in non-weight-bearing regions.
Fig. 3: Features of a subchondral cyst in STR/ort mouse tibia.

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Acknowledgements

The authors would like to thank B. Javaheri and P.M.B. Chan for their initial work in characterizing subchondral cysts in the STR/ort mouse, and A. Boyde of Queen Mary University, London, for producing polarized light microscopy images of subchondral cysts. We would also like to thank P. Louka and R. In’t Zandt of Lund University Bioimaging Centre for helping to guide appreciation of MRI. A.A.P. acknowledges research support from Versus Arthritis (grant number 21900).

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Authors and Affiliations

  1. Skeletal Biology Group, Comparative Biomedical Sciences, Royal Veterinary College, London, UK

    Rebecca T. Hansen, Chantal Chenu & Andrew A. Pitsillides

  2. Institute for Infection and Immunity, St George’s, University of London, London, UK

    Nidhi Sofat

  3. Department of Rheumatology, St George’s, University Hospitals NHS Foundation Trust, London, UK

    Nidhi Sofat

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R.T.H. researched data for the article. A.A.P and R.T.H. contributed substantially to discussion of the content and wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Andrew A. Pitsillides.

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Hansen, R.T., Chenu, C., Sofat, N. et al. Bone marrow lesions: plugging the holes in our knowledge using animal models. Nat Rev Rheumatol 19, 429–445 (2023). https://doi.org/10.1038/s41584-023-00971-z

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