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Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis

Nature Reviews Rheumatology volume 16, pages 193–207 (2020)Cite this article

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Abstract

Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in ‘overuse’ injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.

Key points

  • Mechanical loading is a biological stressor that elicits a homeostatic response to ensure the health and survival of the cells and/or tissues it is applied to.

  • Tissues that encounter high amounts of mechanical stress are prone to damage, especially the tendon and ligament entheses.

  • The immune system is crucial in responding to and orchestrating the repair of damaged tendons and ligaments.

  • Mechanical loading is a well-defined factor in the immunopathology of tendon and ligament disorders such as tendinopathy.

  • Mechanical loading is associated with the onset of chronic inflammatory arthritis, including spondyloarthritis (SpA) and rheumatoid arthritis (RA).

  • Microdamage associated with mechanical loading potentially focuses systemic autoimmune disease on the joint in the initiating phases of SpA and RA.

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Fig. 1: The anatomy of tendons and ligaments in the peripheral and axial skeletons.
Fig. 2: Mechanical forces exerted on tendons and ligaments.
Fig. 3: Proposed tenocyte response mechanisms to mechanical stress.
Fig. 4: The tendon and ligament tissue repair process.
Fig. 5: Proposed model of the relationship between mechanical stress and inflammatory arthritis.

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Article 07 January 2021

Neal L. Millar, Karin G. Silbernagel, … Scott A. Rodeo

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Acknowledgements

The work of I.B.M. is supported by the Versus Arthritis Centre of Excellence for Rheumatoid Arthritis Pathogenesis. The work of H.A. is supported by the Japan Agency for Medical Research and Development (Core Research for Evolutional Science and Technology grants) and U.S. National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants AR050631 and AR065379). The work of D.E. is supported by FWO-VI, Research Council of Ghent University and Interuniversity Attraction Pole grant Devrepair from Belspo Agency (project P7/07) and an FWO Excellence of Science (EOS) Grant.

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Authors and Affiliations

  1. Molecular Immunology and Inflammation Unit, VIB Centre for Inflammation Research, Ghent University, Ghent, Belgium

    Eric Gracey, Arne Burssens, Isabelle Cambré & Dirk Elewaut

  2. Department of Rheumatology, Ghent University Hospital, Ghent, Belgium

    Eric Gracey, Isabelle Cambré & Dirk Elewaut

  3. Department of Orthopaedics and Traumatology, Universitair Ziekenhuis Gent, University of Ghent, Ghent, Belgium

    Arne Burssens

  4. Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Georg Schett

  5. Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

  6. Skeletal Biology and Engineering Research Centre, KU Leuven, Leuven, Belgium

    Rik Lories

  7. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK

    Iain B. McInnes

  8. Department of Molecular Medicine, The Scripps Research Institute, San Diego, CA, USA

    Hiroshi Asahara

  9. Department of Systems BioMedicine, Graduate School of Medical and Dental Sciences, Tokyo, Japan

    Hiroshi Asahara

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Contributions

E.G. and A.B. researched data for the article. E.G., A.B. and I.C. wrote the article. All authors provided a substantial contribution to discussions of content and reviewed or edited the article before submission.

Corresponding authors

Correspondence to Eric Gracey or Dirk Elewaut.

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Competing interests

G.S. declares he has received funding from BMS, Celgene, Janssen, Novartis and UCB in the area of psoriatic arthritis research. R.L. declares he has received consultancy, speaker’s fees or research support from Celgene, Eli-Lilly, Janssen, Novartis and UCB in the areas of psoriatic arthritis and spondyloarthritis research. I.B.M. declares he has received funding from BMS, Celgene, Janssen, Novartis and UCB in the area of psoriatic arthritis research. D.E. declares he has received funding from Boehringer Ingelheim, Janssen, Novartis and Pfizer in the areas of psoriatic arthritis and spondyloarthritis research. The other authors declare no competing interests.

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Glossary

Force

A vector quantity that describes the action of one structure on another; measured in Newtons.

Strain

Deformation that occurs at a point in a structure under loading; measured as the percentage change in length from the resting state.

Load

The sum of all force components acting on an object or body.

Mechanical stress

Mechanical load acting on cells or tissues as a physical stressor that elicits a biological response to ensure homeostasis.

Stress

The force per unit area that develops within a structure in response to externally applied loads; measured in Newtons per metre squared or Megapascals.

Periosteum

A fibrous tissue that envelops non-joint surfaces of bone and contains supportive tissue for the cortical bone, such as blood vessels and nerves.

Metaphyses

The flare (or cone-shaped) portion of long bones that connects the diaphysis to the growth plate.

Diaphyses

The conical shaft of long bones.

Epiphyses

The portion of bones above the growth plate that interfaces with other bones to form the joint.

Strength

The maximum amount of force that a material can absorb before failure.

Modulus

The ratio of stress to strain in the elastic region of a stress–strain curve.

Stiffness

The ratio of load to elongation in the elastic region of a stress–strain curve.

Mechanotransduction

The processes through which cells sense mechanical force and translate it into biological responses.

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Gracey, E., Burssens, A., Cambré, I. et al. Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis. Nat Rev Rheumatol 16, 193–207 (2020). https://doi.org/10.1038/s41584-019-0364-x

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