Inflammatory mechanisms in tendinopathy – towards translation

Key Points

  • Tendinopathy is a complex multi-faceted tendon pathology commonly associated with overuse

  • Most current treatments for tendinopathy are neither effective nor evidence-based

  • Many recent studies have highlighted inflammatory cell infiltrates in both animal and human tendon disease

  • The potential roles of inflammatory mediators acting on the resident tenocytes are the source of some controversy and require in-depth investigation using in vitro and in vivo models

  • Understanding the key inflammatory pathways affecting extracellular matrix regulation and homeostasis are critical in designing future targeted therapies for tendinopathy

Abstract

Tendinopathy is a multifactorial spectrum of tendon disorders that affects different anatomical sites and is characterized by activity-related tendon pain. These disorders are common, account for a high proportion (30%) of referrals to musculoskeletal practitioners and confer a large socioeconomic burden of disease. Our incomplete understanding of the mechanisms underpinning tendon pathophysiology continues to hamper the development of targeted therapies, which have been successful in other areas of musculoskeletal medicine. Debate remains among clinicians about the role of an inflammatory process in tendinopathy owing to a lack of clinical correlation. The advent of modern molecular techniques has highlighted the presence of immune cells and inflammatory mechanisms throughout the spectrum of tendinopathy in both animal and human models of disease. Key inflammatory mediators — such as cytokines, nitric oxide, prostaglandins and lipoxins — play crucial parts in modulating changes in the extracellular matrix within tendinopathy. Understanding the links between inflammatory mechanisms, tendon homeostasis and resolution of tendon damage will be crucial in developing novel therapeutics for human tendon disease.

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Figure 1: Pathological and clinical features of tendinopathy.
Figure 2: Immunobiology of tendinopathy.
Figure 3: Inflammatory mechanisms in tendinopathy.

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Acknowledgements

N.L.M is supported by a Wellcome Trust Postdoctoral Fellowship (WT100651MA) and grants from Arthritis Research UK (Ref 21346) and the Royal College of Surgeons of Edinburgh.

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N.L.M. researched data for the article. N.L.M. and I.B.M. contributed substantially to discussions of the content and wrote the article. All of the authors reviewed and edited the manuscript before submission.

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PowerPoint slides

Glossary

Enthesopathy

Injury to the enthesis, the portion of tendon at the bone–tendon junction site.

TNFΔARE mice

Mouse model in which systemic overexpression of TNF leads to the development of inflammation.

Mid substance

Midportion of a tendon.

Eccentric contraction

Phase of contraction that occurs as the muscle lengthens.

Isometric contraction

Type of contraction during which muscle length does not change (as opposed to concentric or eccentric contractions).

Extracorpeal shockwave therapy

Use of high-amplitude pulses of mechanical energy, similar to soundwaves, to treat tendinopathic lesions.

Debridement

Surgical removal of degenerative tendon tissue.

Microcautery

Micro-debridement of diseased areas of tendon tissue using a high-temperature fine-tipped instrument.

Fibrocartilaginous change

A process in which chondrogenesis occurs in an area of tendon and the structure of the cells changes to chondrocytes.

Patellar tendinopathy

A common overuse injury, caused by repeated stress on the patellar (kneecap) tendon.

Alarmins

Molecules released from a damaged or diseased cell that stimulate an immune response.

Full-thickness rotator cuff tears

Tearing of one or more of the rotator cuff tendons whereby the tendon no longer fully attaches to the head of the humerus.

Cyclic tensile strain

The distribution of forces that change over time in a repetitive fashion.

Cyclic loading

The application of repeated stresses, strains or stress intensities.

Nociceptors

Sensory nerve cells that respond to damaging or potentially damaging stimuli by sending signals to the spinal cord and brain.

Carrageenan-induced tendinopathy

Injection of a family of carrageenans, linear sulfated polysaccharides that are extracted from red edible seaweeds, directly into a mouse tendon to establish tendinopathy.

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Millar, N., Murrell, G. & McInnes, I. Inflammatory mechanisms in tendinopathy – towards translation. Nat Rev Rheumatol 13, 110–122 (2017). https://doi.org/10.1038/nrrheum.2016.213

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