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Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis

Nature Reviews Rheumatology volume 18, pages 67–84 (2022)Cite this article

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Abstract

Mechanical stimuli have fundamental roles in articular cartilage during health and disease. Chondrocytes respond to the physical properties of the cartilage extracellular matrix (ECM) and the mechanical forces exerted on them during joint loading. In osteoarthritis (OA), catabolic processes degrade the functional ECM and the composition and viscoelastic properties of the ECM produced by chondrocytes are altered. The abnormal loading environment created by these alterations propagates cell dysfunction and inflammation. Chondrocytes sense their physical environment via an array of mechanosensitive receptors and channels that activate a complex network of downstream signalling pathways to regulate several cell processes central to OA pathology. Advances in understanding the complex roles of specific mechanosignalling mechanisms in healthy and OA cartilage have highlighted molecular processes that can be therapeutically targeted to interrupt pathological feedback loops. The potential for combining these mechanosignalling targets with the rapidly expanding field of smart mechanoresponsive biomaterials and delivery systems is an emerging paradigm in OA treatment. The continued advances in this field have the potential to enable restoration of healthy mechanical microenvironments and signalling through the development of precision therapeutics, mechanoregulated biomaterials and drug systems in the near future.

Key points

  • Mechanical forces are a critical environmental factor for maintaining joint homeostasis, determining cell phenotype, inflammatory responses and the tightly regulated anabolic–catabolic signalling axis essential for cartilage homeostasis.

  • Chondrocytes sense their mechanical environment through numerous direct and indirect mechanisms that regulate cell function in health and degenerative diseases, such as osteoarthritis.

  • Targeted inhibition of mechanoinflammatory signalling pathways or restoration of functional chondroprotective extracellular matrix environments in osteoarthritis could prevent extracellular matrix degradation and promote reparative anabolic processes.

  • Development of self-regulating and mechanically responsive biomaterials and drug delivery systems offer advanced ‘on-demand’ therapeutic approaches for the treatment of osteoarthritis.

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Fig. 1: Articular cartilage composition and structure.
Fig. 2: Growth factor signalling in chondrocytes.
Fig. 3: Chondrocyte mechanosignalling.
Fig. 4: Mechanoinflammation signalling pathways in chondrocytes in osteoarthritis.
Fig. 5: Mechanoresponsive therapeutics for the treatment of osteoarthritis.

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Acknowledgements

T.H. is in receipt of a Marie Skłodowska-Curie Individual Fellowship from the European Commission through the Horizon 2020 project ChondroCONNECT (project ID: 894837). The work of D.C.K. is funded by Science Foundation Ireland under the European Regional Development Fund CÚRAM (13/RC/2073) and the Irish Research Council Government of Ireland Postgraduate Programme (GOIPG/2018/371). C.M.C. recognizes funding from the Irish Health Research Board (ILP-POR-2019-023 and ILP-POR-2017-032). F.J.O'B. acknowledges funding from the European Commission Horizon 2020 research and innovation programme under the European Research Council Advanced Grant (agreement ID: 788753, ReCaP) and from the Irish Health Research Board (ILP-POR-2017-032).

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  1. These authors contributed equally: Tom Hodgkinson, Domnhall C. Kelly.

Authors and Affiliations

  1. Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland

    Tom Hodgkinson, Domhnall C. Kelly, Caroline M. Curtin & Fergal J. O’Brien

  2. Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and Trinity College Dublin, Dublin, Ireland

    Tom Hodgkinson, Caroline M. Curtin & Fergal J. O’Brien

  3. Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland

    Domhnall C. Kelly & Fergal J. O’Brien

  4. Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    Caroline M. Curtin & Fergal J. O’Brien

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Glossary

Shear

A force or stress that is applied coplanar with the cross-section of the tissue.

Stretch

Deformation resulting in the final length of a material being greater than the initial length.

Pressure

A force applied acting inwards normal to any surface divided by the area of the surface.

Strain

The deformation of a material from stress.

F-actin rarefication

A process resulting in a reduction in F-actin abundance within a cell.

Tribology

The science and engineering of interacting surfaces (wear, friction and lubrication) and how they behave in relative motion.

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Hodgkinson, T., Kelly, D.C., Curtin, C.M. et al. Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat Rev Rheumatol 18, 67–84 (2022). https://doi.org/10.1038/s41584-021-00724-w

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