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Tendinopathy

An Author Correction to this article was published on 03 February 2021

This article has been updated

Abstract

Tendinopathy describes a complex multifaceted pathology of the tendon, characterized by pain, decline in function and reduced exercise tolerance. The most common overuse tendinopathies involve the rotator cuff tendon, medial and lateral elbow epicondyles, patellar tendon, gluteal tendons and the Achilles tendon. The prominent histological and molecular features of tendinopathy include disorganization of collagen fibres, an increase in the microvasculature and sensory nerve innervation, dysregulated extracellular matrix homeostasis, increased immune cells and inflammatory mediators, and enhanced cellular apoptosis. Although diagnosis is mostly achieved based on clinical symptoms, in some cases, additional pain-provoking tests and imaging might be necessary. Management consists of different exercise and loading programmes, therapeutic modalities and surgical interventions; however, their effectiveness remains ambiguous. Future research should focus on elucidating the key functional pathways implicated in clinical disease and on improved rehabilitation protocols.

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Fig. 1: Structural changes of tendons in tendinopathy.
Fig. 2: Common sites of tendinopathy.
Fig. 3: Pathophysiology of tendinopathy.
Fig. 4: Molecular mechanisms of tendinopathy.
Fig. 5: Management of tendinopathy.

Change history

  • 03 February 2021

    A Correction to this paper has been published: https://doi.org/10.1038/s41572-021-00251-8.

References

  1. 1.

    Riley, G. Tendinopathy–from basic science to treatment. Nat. Clin. Pract. Rheumatol. 4, 82–89 (2008).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Lin, T. W., Cardenas, L. & Soslowsky, L. J. Biomechanics of tendon injury and repair. J. Biomech. 37, 865–877 (2004).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Magnusson, S. P., Langberg, H. & Kjaer, M. The pathogenesis of tendinopathy: balancing the response to loading. Nat. Rev. Rheumatol. 6, 262–268 (2010).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    September, A., Rahim, M. & Collins, M. Towards an understanding of the genetics of tendinopathy. Adv. Exp. Med. Biol. 920, 109–116 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Hopkins, C. et al. Critical review on the socio-economic impact of tendinopathy. Asia Pac. J. Sports Med. Arthrosc. Rehabil. Technol. 4, 9–20 (2016). This paper highlights the socioeconomic importance of tendinopathy in medical practice.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Albers, I. S., Zwerver, J., Diercks, R. L., Dekker, J. H. & Van den Akker-Scheek, I. Incidence and prevalence of lower extremity tendinopathy in a Dutch general practice population: a cross sectional study. BMC Musculoskelet. Disord. 17, 16 (2016).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Riel, H., Lindstrom, C. F., Rathleff, M. S., Jensen, M. B. & Olesen, J. L. Prevalence and incidence rate of lower-extremity tendinopathies in a Danish general practice: a registry-based study. BMC Musculoskelet. Disord. 20, 239 (2019).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Linsell, L. et al. Prevalence and incidence of adults consulting for shoulder conditions in UK primary care; patterns of diagnosis and referral. Rheumatology 45, 215–221 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    van der Windt, D. A., Koes, B. W., de Jong, B. A. & Bouter, L. M. Shoulder disorders in general practice: incidence, patient characteristics, and management. Ann. Rheum. Dis. 54, 959–964 (1995).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Kujala, U. M., Sarna, S. & Kaprio, J. Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes. Clin. J. Sport. Med. 15, 133–135 (2005).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Simpson, M., Rio, E. & Cook, J. At what age do children and adolescents develop lower limb tendon pathology or tendinopathy? A systematic review and meta-analysis. Sports Med. 46, 545–557 (2016).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Scott, A. et al. Lipids, adiposity and tendinopathy: is there a mechanistic link? Critical review. Br. J. Sports Med. 49, 984–988 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Abate, M., Schiavone, C., Salini, V. & Andia, I. Occurrence of tendon pathologies in metabolic disorders. Rheumatology 52, 599–608 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    van der Vlist, A. C., Breda, S. J., Oei, E. H. G., Verhaar, J. A. N. & de Vos, R. J. Clinical risk factors for Achilles tendinopathy: a systematic review. Br. J. Sports Med. 53, 1352–1361 (2019).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Ranger, T. A., Wong, A. M., Cook, J. L. & Gaida, J. E. Is there an association between tendinopathy and diabetes mellitus? A systematic review with meta-analysis. Br. J. Sports Med. 50, 982–989 (2016).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Taylor, B., Cheema, A. & Soslowsky, L. Tendon pathology in hypercholesterolemia and familial hypercholesterolemia. Curr. Rheumatol. Rep. 19, 76 (2017).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    O’Neill, S., Watson, P. J. & Barry, S. A Delphi study of risk factors for achilles tendinopathy–opinions of world tendon experts. Int. J. Sports Phys. Ther. 11, 684–697 (2016).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Millar, N. L., Siebert, S. & McInnes, I. B. Europe rules on harm from fluoroquinolone antibiotics. Nature 566, 326 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Macedo, C. S. G. et al. Physical therapy service delivered in the polyclinic during the Rio 2016 paralympic games. Phys. Ther. Sport. 36, 62–67 (2019).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Florit, D. et al. Incidence of tendinopathy in team sports in a multidisciplinary sports club over 8 seasons. J. Sports Sci. Med. 18, 780–788 (2019).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Francis, P., Whatman, C., Sheerin, K., Hume, P. & Johnson, M. I. The proportion of lower limb running injuries by gender, anatomical location and specific pathology: a systematic review. J. Sports Sci. Med. 18, 21–31 (2019).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Sanders, T. L. Jr. et al. The epidemiology and health care burden of tennis elbow: a population-based study. Am. J. Sports Med. 43, 1066–1071 (2015).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Abat, F. et al. Current trends in tendinopathy: consensus of the ESSKA basic science committee. Part I: biology, biomechanics, anatomy and an exercise-based approach. J. Exp. Orthop. 4, 18 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Vaughn, N. H., Stepanyan, H., Gallo, R. A. & Dhawan, A. Genetic factors in tendon injury: a systematic review of the literature. Orthop. J. Sports Med. 5, 2325967117724416 (2017).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Brown, K. L. et al. Polymorphisms within the COL5A1 gene and regulators of the extracellular matrix modify the risk of Achilles tendon pathology in a British case-control study. J. Sports Sci. 35, 1475–1483 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Mokone, G. G., Schwellnus, M. P., Noakes, T. D. & Collins, M. The COL5A1 gene and Achilles tendon pathology. Scand. J. Med. Sci. Sports 16, 19–26 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Nie, G. et al. Additional evidence supports association of common genetic variants in MMP3 and TIMP2 with increased risk of chronic Achilles tendinopathy susceptibility. J. Sci. Med. Sport. 22, 1074–1078 (2019).

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Longo, U. G. et al. Genetic basis of rotator cuff injury: a systematic review. BMC Med. Genet. 20, 149 (2019).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Dabija, D. I., Gao, C., Edwards, T. L., Kuhn, J. E. & Jain, N. B. Genetic and familial predisposition to rotator cuff disease: a systematic review. J. Shoulder Elb. Surg. 26, 1103–1112 (2017).

    Google Scholar 

  30. 30.

    Tran, P. H. T. et al. Early development of tendinopathy in humans: sequence of pathological changes in structure and tissue turnover signaling. FASEB J. 34, 776–788 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Millar, N. L. et al. Inflammation is present in early human tendinopathy. Am. J. Sports Med. 38, 2085–2091 (2010).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    O’Brien, M. Structure and metabolism of tendons. Scand. J. Med. Sci. Sports 7, 55–61 (1997).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Subramanian, A., Kanzaki, L. F., Galloway, J. L. & Schilling, T. F. Mechanical force regulates tendon extracellular matrix organization and tenocyte morphogenesis through TGFbeta signaling. eLife 7, e38069 (2018).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Sharma, P. & Maffulli, N. Biology of tendon injury: healing, modeling and remodeling. J. Musculoskelet. Neuronal Interact. 6, 181 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Kjaer, M. et al. Metabolic activity and collagen turnover in human tendon in response to physical activity. J. Musculoskelet. Neuronal Interact. 5, 41–52 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Best, K. T., Lee, F. K., Knapp, E., Awad, H. A. & Loiselle, A. E. Deletion of NFKB1 enhances canonical NF-κB signaling and increases macrophage and myofibroblast content during tendon healing. Sci. Rep. 9, 10926 (2019).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Millar, N. L., Murrell, G. A. & McInnes, I. B. Alarmins in tendinopathy: unravelling new mechanisms in a common disease. Rheumatology 52, 769–779 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Abraham, A. C. et al. Targeting the NF-κB signaling pathway in chronic tendon disease. Sci. Transl. Med. 11, eaav4319 (2019).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Tan, G. K. et al. Tgfβ signaling is critical for maintenance of the tendon cell fate. eLife 9, e52695 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Goodier, H. C. et al. Comparison of transforming growth factor beta expression in healthy and diseased human tendon. Arthritis Res. Ther. 18, 48 (2016).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Kannus, P. & Jozsa, L. Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J. Bone Joint Surg. Am. 73, 1507–1525 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Kannus, P., Jozsa, L. & Jarvinen, M. in Principles and Practice of Orthopaedic Sports Medicine (eds Garrett W. E. Jr, Speer K. P., Kirkendall D. T.) 21-37 (Lippincott Williams and Wilkins, 2000).

  43. 43.

    Maffulli, N., Barrass, V. & Ewen, S. W. Light microscopic histology of Achilles tendon ruptures. A comparison with unruptured tendons. Am. J. Sports Med. 28, 857–863 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Maffulli, N., Ewen, S. W., Waterston, S. W., Reaper, J. & Barrass, V. Tenocytes from ruptured and tendinopathic Achilles tendons produce greater quantities of type III collagen than tenocytes from normal Achilles tendons. An in vitro model of human tendon healing. Am. J. Sports Med. 28, 499–505 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Maeda, E., Noguchi, H., Tohyama, H., Yasuda, K. & Hayashi, K. The tensile properties of collagen fascicles harvested from regenerated and residual tissues in the patellar tendon after removal of the central third. Biomed. Mater. Eng. 17, 77–85 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Guerquin, M. J. et al. Transcription factor EGR1 directs tendon differentiation and promotes tendon repair. J. Clin. Invest. 123, 3564–3576 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Lorda-Diez, C. I., Montero, J. A., Martinez-Cue, C., Garcia-Porrero, J. A. & Hurle, J. M. Transforming growth factors β coordinate cartilage and tendon differentiation in the developing limb mesenchyme. J. Biol. Chem. 284, 29988–29996 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Langberg, H. et al. Eccentric rehabilitation exercise increases peritendinous type I collagen synthesis in humans with Achilles tendinosis. Scand. J. Med. Sci. Sports 17, 61–66 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Heinemeier, K. M., Schjerling, P., Heinemeier, J., Magnusson, S. P. & Kjaer, M. Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb (14)C. FASEB J. 27, 2074–2079 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Heinemeier, K. M. et al. Carbon-14 bomb pulse dating shows that tendinopathy is preceded by years of abnormally high collagen turnover. FASEB J. 32, 4763–4775 (2018). This is a key paper that describes the collagen turnonver in tendinopathy.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Chang, J. et al. Circadian control of the secretory pathway maintains collagen homeostasis. Nat. Cell Biol. 22, 74–86 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Del Buono, A., Oliva, F., Osti, L. & Maffulli, N. Metalloproteases and tendinopathy. Muscles Ligaments Tendons J. 3, 51–57 (2013).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Thorpe, C. T. et al. The interfascicular matrix enables fascicle sliding and recovery in tendon, and behaves more elastically in energy storing tendons. J. Mech. Behav. Biomed. Mater. 52, 85–94 (2015).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Thorpe, C. T., Riley, G. P., Birch, H. L., Clegg, P. D. & Screen, H. R. C. Fascicles and the interfascicular matrix show decreased fatigue life with ageing in energy storing tendons. Acta Biomater. 56, 58–64 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Thorpe, C. T., Birch, H. L., Clegg, P. D. & Screen, H. R. The role of the non-collagenous matrix in tendon function. Int. J. Exp. Pathol. 94, 248–259 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Mouw, J. K., Ou, G. & Weaver, V. M. Extracellular matrix assembly: a multiscale deconstruction. Nat. Rev. Mol. Cell Biol. 15, 771–785 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Screen, H. R., Berk, D. E., Kadler, K. E., Ramirez, F. & Young, M. F. Tendon functional extracellular matrix. J. Orthop. Res. 33, 793–799 (2015).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Murrell, G. A. Oxygen free radicals and tendon healing. J. Shoulder Elb. Surg. 16, S208–S214 (2007).

    Google Scholar 

  59. 59.

    Ray, P. D., Huang, B. W. & Tsuji, Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 24, 981–990 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Bestwick, C. S. & Maffulli, N. Reactive oxygen species and tendinopathy: do they matter? Br. J. Sports Med. 38, 672–674 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Sejersen, M. H., Frost, P., Hansen, T. B., Deutch, S. R. & Svendsen, S. W. Proteomics perspectives in rotator cuff research: a systematic review of gene expression and protein composition in human tendinopathy. PLoS ONE 10, e0119974 (2015).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Murrell, G. A. et al. Modulation of tendon healing by nitric oxide. Inflamm. Res. 46, 19–27 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Szomor, Z. L. et al. Differential expression of cytokines and nitric oxide synthase isoforms in human rotator cuff bursae. Ann. Rheum. Dis. 60, 431–432 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Vasta, S. et al. Role of VEGF, nitric oxide, and sympathetic neurotransmitters in the pathogenesis of tendinopathy: a review of the current evidences. Front. Aging Neurosci. 8, 186 (2016).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Scott, A. et al. Tenocyte responses to mechanical loading in vivo: a role for local insulin-like growth factor 1 signaling in early tendinosis in rats. Arthritis Rheum. 56, 871–881 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Poulsen, R. C., Carr, A. J. & Hulley, P. A. Protection against glucocorticoid-induced damage in human tenocytes by modulation of ERK, Akt, and forkhead signaling. Endocrinology 152, 503–514 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Millar, N. L. et al. Hypoxia: a critical regulator of early human tendinopathy. Ann. Rheum. Dis. 71, 302–310 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Schwartz, A. J. et al. p38 MAPK signaling in postnatal tendon growth and remodeling. PLoS ONE 10, e0120044 (2015).

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Lui, P. P. et al. Expression of Wnt pathway mediators in metaplasic tissue in animal model and clinical samples of tendinopathy. Rheumatology 52, 1609–1618 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Theodossiou, S. K. & Schiele, N. R. Models of tendon development and injury. BMC Biomed. Eng. 1, 32 (2019).

    Google Scholar 

  71. 71.

    Yuan, J., Murrell, G. A., Trickett, A. & Wang, M. X. Involvement of cytochrome c release and caspase-3 activation in the oxidative stress-induced apoptosis in human tendon fibroblasts. Biochim. Biophys. Acta 1641, 35–41 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Yuan, J., Murrell, G. A., Wei, A. Q. & Wang, M. X. Apoptosis in rotator cuff tendonopathy. J. Orthop. Res. 20, 1372–1379 (2002).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Millar, N. L., Wei, A. Q., Molloy, T. J., Bonar, F. & Murrell, G. A. Cytokines and apoptosis in supraspinatus tendinopathy. J. Bone Joint Surg. Br. 91, 417–424 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Scott, A. & Bahr, R. Neuropeptides in tendinopathy. Front. Biosci. 14, 2203–2211 (2009).

    CAS  Google Scholar 

  75. 75.

    Alfredson, H., Thorsen, K. & Lorentzon, R. In situ microdialysis in tendon tissue: high levels of glutamate, but not prostaglandin E2 in chronic Achilles tendon pain. Knee Surg. Sports Traumatol. Arthrosc. 7, 378–381 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Franklin, S. L. et al. Up-regulation of glutamate in painful human supraspinatus tendon tears. Am. J. Sports Med. 42, 1955–1962 (2014).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Dean, B. J. et al. Differences in glutamate receptors and inflammatory cell numbers are associated with the resolution of pain in human rotator cuff tendinopathy. Arthritis Res. Ther. 17, 176 (2015).

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Dean, B. J., Snelling, S. J., Dakin, S. G., Javaid, M. K. & Carr, A. J. In vitro effects of glutamate and N-methyl-D-aspartate receptor (NMDAR) antagonism on human tendon derived cells. J. Orthop. Res. 33, 1515–1522 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Millar, N. L., Murrell, G. A. C. & McInnes, I. B. Inflammatory mechanisms in tendinopathy - towards translation. Nat. Rev. Rheumatol. 13, 110–122 (2017). This paper is an important review of the inflammatory mechanisms in tendinopathy pathogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Dakin, S. G., Dudhia, J. & Smith, R. K. Resolving an inflammatory concept: the importance of inflammation and resolution in tendinopathy. Vet. Immunol. Immunopathol. 158, 121–127 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Dakin, S. G. et al. Inflammation activation and resolution in human tendon disease. Sci. Transl. Med. 7, 311ra173 (2015). This paper discusses the potential molecular resolution pathways in tendinopathy pathogenesis.

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Dean, B. J. F., Dakin, S. G., Millar, N. L. & Carr, A. J. Review: Emerging concepts in the pathogenesis of tendinopathy. Surgeon 15, 349–354 (2017).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Dakin, S. G. et al. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nat. Rev. Rheumatol. 14, 714–726 (2018).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Akbar, M. et al. Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis. RMD Open 3, e000456 (2017).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Sunwoo, J. Y., Eliasberg, C. D., Carballo, C. B. & Rodeo, S. A. The role of the macrophage in tendinopathy and tendon healing. J. Orthop. Res. 38, 1666–1675 (2020).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Crowe, L. A. N. et al. S100A8 & S100A9: Alarmin mediated inflammation in tendinopathy. Sci. Rep. 9, 1463 (2019).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Langberg, H., Olesen, J. L., Gemmer, C. & Kjaer, M. Substantial elevation of interleukin-6 concentration in peritendinous tissue, in contrast to muscle, following prolonged exercise in humans. J. Physiol. 542, 985–990 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    John, T. et al. Effect of pro-inflammatory and immunoregulatory cytokines on human tenocytes. J. Orthop. Res. 28, 1071–1077 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Lin, T. W., Cardenas, L. & Soslowsky, L. J. Tendon properties in interleukin-4 and interleukin-6 knockout mice. J. Biomech. 38, 99–105 (2005).

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Foster, P. S. & Mattes, J. IL-21 comes of age. Immunol. Cell Biol. 87, 359–360 (2009).

    CAS  Google Scholar 

  91. 91.

    Jelinsky, S. A. et al. Regulation of gene expression in human tendinopathy. BMC Musculoskelet. Disord. 12, 86 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Kakkar, R., Hei, H., Dobner, S. & Lee, R. T. Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J. Biol. Chem. 287, 6941–6948 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005).

    CAS  Google Scholar 

  94. 94.

    Millar, N. L. et al. MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease. Nat. Commun. 6, 6774 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Millar, N. L. et al. IL-17A mediates inflammatory and tissue remodelling events in early human tendinopathy. Sci. Rep. 6, 27149 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Millar, N. L. et al. Interleukin 17A– a translational target to treat supraspinatus tendinopathy. Arthritis Rheumatol. 70 (Suppl. 10), 404 (2018).

    Google Scholar 

  97. 97.

    Zeng, L. et al. MicroRNA-210 overexpression induces angiogenesis and neurogenesis in the normal adult mouse brain. Gene Ther. 21, 37–43 (2014).

    CAS  Google Scholar 

  98. 98.

    Usman, M. A. et al. The effect of administration of double stranded microRNA-210 on acceleration of Achilles tendon healing in a rat model. J. Orthop. Sci. 20, 538–546 (2015).

    Google Scholar 

  99. 99.

    Watts, A. E. et al. MicroRNA29a treatment improves early tendon injury. Mol. Ther. 25, 2415–2426 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Dakin, S. G. et al. Chronic inflammation is a feature of Achilles tendinopathy and rupture. Br. J. Sports Med. 52, 359–367 (2018).

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Dakin, S. G. et al. Persistent stromal fibroblast activation is present in chronic tendinopathy. Arthritis Res. Ther. 19, 16 (2017).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Bi, Y. et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat. Med. 13, 1219–1227 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Wang, J. H. & Komatsu, I. Tendon stem cells: mechanobiology and development of tendinopathy. Adv. Exp. Med. Biol. 920, 53–62 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Zhang, C., Zhu, J., Zhou, Y., Thampatty, B. P. & Wang, J. H. Tendon stem/progenitor cells and their interactions with extracellular matrix and mechanical loading. Stem Cell Int. 2019, 3674647 (2019).

    Google Scholar 

  105. 105.

    Yin, Z. et al. Single-cell analysis reveals a nestin(+) tendon stem/progenitor cell population with strong tenogenic potentiality. Sci. Adv. 2, e1600874 (2016).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    De Micheli, A. J. et al. Single-cell transcriptomic analysis identifies extensive heterogeneity in the cellular composition of mouse Achilles tendons. Am. J. Physiol. Cell Physiol. 319, C885–C894 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Scott, A. et al. ICON 2019: International Scientific Tendinopathy Symposium consensus: clinical terminology. Br. J. Sports Med. 54, 260–262 (2020).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Reiman, M. et al. The utility of clinical measures for the diagnosis of Achilles tendon injuries: a systematic review with meta-analysis. J. Athl. Train. 49, 820–829 (2014).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Dai, F. & Zeng, R. In Handbook of Clinical Diagnostics (eds Wan X. H., Zeng R.) 205–225 (Springer, 2020).

  110. 110.

    Grimaldi, A. et al. Utility of clinical tests to diagnose MRI-confirmed gluteal tendinopathy in patients presenting with lateral hip pain. Br. J. Sports Med. 51, 519–524 (2017).

    Google Scholar 

  111. 111.

    Hegedus, E. J. et al. Which physical examination tests provide clinicians with the most value when examining the shoulder? Update of a systematic review with meta-analysis of individual tests. Br. J. Sports Med. 46, 964–978 (2012).

    Google Scholar 

  112. 112.

    Salamh, P. & Lewis, J. It is time to put special tests for rotator cuff-related shoulder pain out to pasture. J. Orthop. Sports Phys. Ther. 50, 222–225 (2020).

    Google Scholar 

  113. 113.

    Docking, S. I., Ooi, C. C. & Connell, D. Tendinopathy: is imaging telling us the entire story? J. Orthop. Sports Phys. Ther. 45, 842–852 (2015).

    Google Scholar 

  114. 114.

    Silbernagel, K. G. Does one size fit all when it comes to exercise treatment for Achilles tendinopathy? J. Orthop. Sports Phys. Ther. 44, 42–44 (2014). This paper discusses the potential importance of stratified loading in tendinopathy.

    Google Scholar 

  115. 115.

    Clarsen, B., Myklebust, G. & Bahr, R. Development and validation of a new method for the registration of overuse injuries in sports injury epidemiology: the Oslo Sports Trauma Research Centre (OSTRC) overuse injury questionnaire. Br. J. Sports Med. 47, 495–502 (2013).

    Google Scholar 

  116. 116.

    Chang, Y. J. & Kulig, K. The neuromechanical adaptations to Achilles tendinosis. J. Physiol. 593, 3373–3387 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Andersson, S. H. et al. Preventing overuse shoulder injuries among throwing athletes: a cluster-randomised controlled trial in 660 elite handball players. Br. J. Sports Med. 51, 1073–1080 (2017).

    Google Scholar 

  118. 118.

    Harøy, J. et al. The Adductor Strengthening Programme prevents groin problems among male football players: a cluster-randomised controlled trial. Br. J. Sports Med. 53, 150–157 (2019).

    Google Scholar 

  119. 119.

    Fredberg, U. et al. Prophylactic training in asymptomatic soccer players with ultrasonographic abnormalities in Achilles and patellar tendons: the Danish Super League Study. Am. J. Sports Med. 36, 451–460 (2008).

    Google Scholar 

  120. 120.

    Lim, H. Y. & Wong, S. H. Effects of isometric, eccentric, or heavy slow resistance exercises on pain and function in individuals with patellar tendinopathy: a systematic review. Physiother. Res. Int. 23, e1721 (2018).

    Google Scholar 

  121. 121.

    Beyer, R. et al. Heavy slow resistance versus eccentric training as treatment for Achilles tendinopathy: a randomized controlled trial. Am. J. Sports Med. 43, 1704–1711 (2015).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Pedersen M. T. et al. Implementation of specific strength training among industrial laboratory technicians: long-term effects on back, neck and upper extremity pain. BMC Musculoskelet. Disord. 14, 287 (2013).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Aicale, R., Bisaccia, R. D., Oliviero, A., Oliva, F. & Maffulli, N. Current pharmacological approaches to the treatment of tendinopathy. Expert Opin. Pharmacother. 21, 1467–1477 (2020).

    CAS  Google Scholar 

  124. 124.

    Andres, B. M. & Murrell, G. A. Treatment of tendinopathy: what works, what does not, and what is on the horizon. Clin. Orthop. Relat. Res. 466, 1539–1554 (2008). This paper is an important review of the various treatments available for tendinopathy.

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Visnes, H. & Bahr, R. The evolution of eccentric training as treatment for patellar tendinopathy (jumper’s knee): a critical review of exercise programmes. Br. J. Sports Med. 41, 217–223 (2007).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Murtaugh, B. & Ihm, J. M. Eccentric training for the treatment of tendinopathies. Curr. Sports Med. Rep. 12, 175–182 (2013).

    Google Scholar 

  127. 127.

    Camargo, P. R., Alburquerque-Sendín, F. & Salvini, T. F. Eccentric training as a new approach for rotator cuff tendinopathy: review and perspectives. World J. Orthop. 5, 634–644 (2014).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    Stanish, W. D., Rubinovich, R. M. & Curwin, S. Eccentric exercise in chronic tendinitis. Clin. Orthop. Relat. Res. 208, 65–68 (1986).

    Google Scholar 

  129. 129.

    Alfredson, H., Pietila, T., Jonsson, P. & Lorentzon, R. Heavy-load eccentric calf muscle training for the treatment of chronic Achilles tendinosis. Am. J. Sports Med. 26, 360–366 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Silbernagel, K. G., Thomee, R., Eriksson, B. I. & Karlsson, J. Continued sports activity, using a pain-monitoring model, during rehabilitation in patients with Achilles tendinopathy: a randomized controlled study. Am. J. Sports Med. 35, 897–906 (2007).

    Google Scholar 

  131. 131.

    Kongsgaard, M. et al. Corticosteroid injections, eccentric decline squat training and heavy slow resistance training in patellar tendinopathy. Scand. J. Med. Sci. Sports 19, 790–802 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Mellor, R. et al. Education plus exercise versus corticosteroid injection use versus a wait and see approach on global outcome and pain from gluteal tendinopathy: prospective, single blinded, randomised clinical trial. BMJ 361, k1662 (2018).

    PubMed  PubMed Central  Google Scholar 

  133. 133.

    Coombes, B. K., Bisset, L. & Vicenzino, B. Management of lateral elbow tendinopathy: one size does not fit all. J. Orthop. Sports Phys. Ther. 45, 938–949 (2015).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Pieters, L. et al. An update of systematic reviews examining the effectiveness of conservative physical therapy interventions for subacromial shoulder pain. J. Orthop. Sports Phys. Ther. 50, 131–141 (2020).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Mallows, A., Debenham, J., Walker, T. & Littlewood, C. Association of psychological variables and outcome in tendinopathy: a systematic review. Br. J. Sports Med. 51, 743–748 (2017).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Bohm, S., Mersmann, F. & Arampatzis, A. Human tendon adaptation in response to mechanical loading: a systematic review and meta-analysis of exercise intervention studies on healthy adults. Sports Med. Open 1, 7 (2015).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Rio, E. et al. Isometric exercise induces analgesia and reduces inhibition in patellar tendinopathy. Br. J. Sports Med. 49, 1277–1283 (2015).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    Holden, S. et al. Isometric exercise and pain in patellar tendinopathy: a randomized crossover trial. J. Sci. Med. Sport 23, 208–214 (2020).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    O’Neill, S. et al. Acute sensory and motor response to 45-s heavy isometric holds for the plantar flexors in patients with Achilles tendinopathy. Knee Surg. Sports Traumatol. Arthrosc. 27, 2765–2773 (2019).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Riel, H. et al. The effect of isometric exercise on pain in individuals with plantar fasciopathy: a randomized crossover trial. Scand. J. Med. Sci. Sports 28, 2643–2650 (2018).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Gravare Silbernagel, K., Vicenzino, B. T., Rathleff, M. S. & Thorborg, K. Isometric exercise for acute pain relief: is it relevant in tendinopathy management? Br. J. Sports Med. 53, 1330–1331 (2019). This paper discusses the relative merits of isometic exercise in tendinoapthy.

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Frohm, A., Saartok, T., Halvorsen, K. & Renstrom, P. Eccentric treatment for patellar tendinopathy: a prospective randomised short-term pilot study of two rehabilitation protocols. Br. J. Sports Med. 41, e7 (2007).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Kongsgaard, M. et al. Fibril morphology and tendon mechanical properties in patellar tendinopathy: effects of heavy slow resistance training. Am. J. Sports Med. 38, 749–756 (2010).

    Google Scholar 

  144. 144.

    Silbernagel, K. G., Thomee, R., Thomee, P. & Karlsson, J. Eccentric overload training for patients with chronic Achilles tendon pain–a randomised controlled study with reliability testing of the evaluation methods. Scand. J. Med. Sci. Sports 11, 197–206 (2001).

    CAS  Google Scholar 

  145. 145.

    Habets, B. & van Cingel, R. E. Eccentric exercise training in chronic mid-portion Achilles tendinopathy: a systematic review on different protocols. Scand. J. Med. Sci. Sports 25, 3–15 (2015).

    CAS  Google Scholar 

  146. 146.

    Silbernagel, K. G., Thomee, R. & Karlsson, J. Cross-cultural adaptation of the VISA-A questionnaire, an index of clinical severity for patients with Achilles tendinopathy, with reliability, validity and structure evaluations. BMC Musculoskelet. Disord. 6, 12 (2005).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Scott, A. et al. Sports and exercise-related tendinopathies: a review of selected topical issues by participants of the second International Scientific Tendinopathy Symposium (ISTS) Vancouver 2012. Br. J. Sports Med. 47, 536–544 (2013).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Malliaras, P., Barton, C. J., Reeves, N. D. & Langberg, H. Achilles and patellar tendinopathy loading programmes: a systematic review comparing clinical outcomes and identifying potential mechanisms for effectiveness. Sports Med. 43, 267–286 (2013). This paper is an important systematic review of loading programmes in tendinopathy.

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Littlewood, C., Malliaras, P. & Chance-Larsen, K. Therapeutic exercise for rotator cuff tendinopathy: a systematic review of contextual factors and prescription parameters. Int. J. Rehabil. Res. 38, 95–106 (2015).

    Google Scholar 

  150. 150.

    de Jonge, S. et al. The tendon structure returns to asymptomatic values in nonoperatively treated achilles tendinopathy but is not associated with symptoms: a prospective study. Am. J. Sports Med. 43, 2950–2958 (2015).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Rees, J. D., Wilson, A. M. & Wolman, R. L. Current concepts in the management of tendon disorders. Rheumatology 45, 508–521 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Irby, A., Gutierrez, J., Chamberlin, C., Thomas, S. J. & Rosen, A. B. Clinical management of tendinopathy: a systematic review of systematic reviews evaluating the effectiveness of tendinopathy treatments. Scand. J. Med. Sci. Sports 30, 1810–1826 (2020).

    PubMed  PubMed Central  Google Scholar 

  153. 153.

    Dean, B. J. et al. The risks and benefits of glucocorticoid treatment for tendinopathy: a systematic review of the effects of local glucocorticoid on tendon. Semin. Arthritis Rheum. 43, 570–576 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Puzzitiello, R. N. et al. Adverse impact of corticosteroid injection on rotator cuff tendon health and repair: a systematic review. Arthroscopy 36, 1468–1475 (2019).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Coombes, B. K., Bisset, L., Brooks, P., Khan, A. & Vicenzino, B. Effect of corticosteroid injection, physiotherapy, or both on clinical outcomes in patients with unilateral lateral epicondylalgia: a randomized controlled trial. JAMA 309, 461–469 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Lin, M. T. et al. Comparative effectiveness of injection therapies in rotator cuff tendinopathy: a systematic review, pairwise and network meta-analysis of randomized controlled trials. Arch. Phys. Med. Rehabil. 100, 336–349.e15 (2019).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Mohamadi, A., Chan, J. J., Claessen, F. M., Ring, D. & Chen, N. C. Corticosteroid injections give small and transient pain relief in rotator cuff tendinosis: a meta-analysis. Clin. Orthop. Relat. Res. 475, 232–243 (2017).

    PubMed  PubMed Central  Google Scholar 

  158. 158.

    Claessen, F., Heesters, B. A., Chan, J. J., Kachooei, A. R. & Ring, D. A meta-analysis of the effect of corticosteroid injection for enthesopathy of the extensor carpi radialis brevis origin. J. Hand Surg. Am. 41, 988–998,e2 (2016).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Coombes, B. K., Bisset, L. & Vicenzino, B. Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials. Lancet 376, 1751–1767 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Everhart, J. S. et al. Treatment options for patellar tendinopathy: a systematic review. Arthroscopy 33, 861–872 (2017).

    Google Scholar 

  161. 161.

    Boesen, A. P., Langberg, H., Hansen, R., Malliaras, P. & Boesen, M. I. High volume injection with and without corticosteroid in chronic midportion Achilles tendinopathy. Scand. J. Med. Sci. Sports 29, 1223–1231 (2019).

    PubMed  PubMed Central  Google Scholar 

  162. 162.

    Gross, C. E., Hsu, A. R., Chahal, J. & Holmes, G. B. Jr. Injectable treatments for noninsertional achilles tendinosis: a systematic review. Foot Ankle Int. 34, 619–628 (2013).

    Google Scholar 

  163. 163.

    Kearney, R. S., Parsons, N., Metcalfe, D. & Costa, M. L. Injection therapies for Achilles tendinopathy. Cochrane Database Syst. Rev. 5, CD010960 (2015).

    Google Scholar 

  164. 164.

    Fredberg, U. et al. Ultrasonography as a tool for diagnosis, guidance of local steroid injection and, together with pressure algometry, monitoring of the treatment of athletes with chronic jumper’s knee and Achilles tendinitis: a randomized, double-blind, placebo-controlled study. Scand. J. Rheumatol. 33, 94–101 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Mahler, F. & Fritschy, D. Partial and complete ruptures of the Achilles tendon and local corticosteroid injections. Br. J. Sports Med. 26, 7–14 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Vallone, G. & Vittorio, T. Complete Achilles tendon rupture after local infiltration of corticosteroids in the treatment of deep retrocalcaneal bursitis. J. Ultrasound 17, 165–167 (2014).

    PubMed  PubMed Central  Google Scholar 

  167. 167.

    Le, A. D. K., Enweze, L., DeBaun, M. R. & Dragoo, J. L. Current clinical recommendations for use of platelet-rich plasma. Curr. Rev. Musculoskelet. Med. 11, 624–634 (2018).

    PubMed  PubMed Central  Google Scholar 

  168. 168.

    Zhou, Y. & Wang, J. H. PRP treatment efficacy for tendinopathy: a review of basic science studies. Biomed. Res. Int. 2016, 9103792 (2016).

    PubMed  PubMed Central  Google Scholar 

  169. 169.

    Mishra, A. K. et al. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am. J. Sports Med. 42, 463–471 (2014).

    PubMed  PubMed Central  Google Scholar 

  170. 170.

    Arirachakaran, A. et al. Platelet-rich plasma versus autologous blood versus steroid injection in lateral epicondylitis: systematic review and network meta-analysis. J. Orthop. Traumatol. 17, 101–112 (2016).

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Gosens, T., Peerbooms, J. C., van Laar, W. & den Oudsten, B. L. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am. J. Sports Med. 39, 1200–1208 (2011).

    PubMed  PubMed Central  Google Scholar 

  172. 172.

    Peerbooms, J. C., Sluimer, J., Bruijn, D. J. & Gosens, T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year follow-up. Am. J. Sports Med. 38, 255–262 (2010).

    PubMed  PubMed Central  Google Scholar 

  173. 173.

    de Vos, R. J., Windt, J. & Weir, A. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br. J. Sports Med. 48, 952–956 (2014).

    PubMed  PubMed Central  Google Scholar 

  174. 174.

    Liddle, A. D. & Rodriguez-Merchan, E. C. Platelet-rich plasma in the treatment of patellar tendinopathy: a systematic review. Am. J. Sports Med. 43, 2583–2590 (2015).

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    Scott, A. et al. Platelet-rich plasma for patellar tendinopathy: a randomized controlled trial of leukocyte-rich PRP or leukocyte-poor PRP versus saline. Am. J. Sports Med. 47, 1654–1661 (2019).

    Google Scholar 

  176. 176.

    Nauwelaers, A. K., Van Oost, L. & Peers, K. Evidence for the use of PRP in chronic midsubstance Achilles tendinopathy: a systematic review with meta-analysis. Foot Ankle Surg. https://doi.org/10.1016/j.fas.2020.07.009 (2020).

    Article  Google Scholar 

  177. 177.

    Liu, C. J., Yu, K. L., Bai, J. B., Tian, D. H. & Liu, G. L. Platelet-rich plasma injection for the treatment of chronic Achilles tendinopathy: a meta-analysis. Medicine 98, e15278 (2019).

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Carr, A. J. et al. Platelet-rich plasma injection with arthroscopic acromioplasty for chronic rotator cuff tendinopathy: a randomized controlled trial. Am. J. Sports Med. 43, 2891–2897 (2015).

    Google Scholar 

  179. 179.

    Franchini, M. et al. Efficacy of platelet-rich plasma as conservative treatment in orthopaedics: a systematic review and meta-analysis. Blood Transfus. 16, 502–513 (2018).

    PubMed  PubMed Central  Google Scholar 

  180. 180.

    Challoumas, D. et al. Topical glyceryl trinitrate for the treatment of tendinopathies: a systematic review. Br. J. Sports Med. 53, 251–262 (2019).

    Google Scholar 

  181. 181.

    Cotler, H. B., Chow, R. T., Hamblin, M. R. & Carroll, J. The use of low level laser therapy (LLLT) for musculoskeletal pain. MOJ Orthop. Rheumatol. 2, 188–194 (2015).

    Google Scholar 

  182. 182.

    Mamais, I., Papadopoulos, K., Lamnisos, D. & Stasinopoulos, D. Effectiveness of low level laser therapy (LLLT) in the treatment of lateral elbow tendinopathy (LET): an umbrella review. Laser Ther. 27, 174–186 (2018).

    PubMed  PubMed Central  Google Scholar 

  183. 183.

    Bjordal, J. M. et al. A systematic review with procedural assessments and meta-analysis of low level laser therapy in lateral elbow tendinopathy (tennis elbow). BMC Musculoskelet. Disord. 9, 75 (2008).

    PubMed  PubMed Central  Google Scholar 

  184. 184.

    Lian, J. et al. Comparative efficacy and safety of nonsurgical treatment options for enthesopathy of the extensor carpi radialis brevis: a systematic review and meta-analysis of randomized placebo-controlled trials. Am. J. Sports Med. 47, 3019–3029 (2019).

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    de Jesus, J. F. et al. Low-level laser therapy (780 nm) on VEGF modulation at partially injured Achilles tendon. Photomed. Laser Surg. 34, 331–335 (2016).

    PubMed  PubMed Central  Google Scholar 

  186. 186.

    Gomes, C. et al. Effects of low-level laser therapy on the modulation of tissue temperature and hyperalgesia following a partial Achilles tendon injury in rats. J. Cosmet. Laser Ther. 19, 391–396 (2017).

    Google Scholar 

  187. 187.

    Haslerud, S., Magnussen, L. H., Joensen, J., Lopes-Martins, R. A. & Bjordal, J. M. The efficacy of low-level laser therapy for shoulder tendinopathy: a systematic review and meta-analysis of randomized controlled trials. Physiother. Res. Int. 20, 108–125 (2015).

    Google Scholar 

  188. 188.

    Barker-Davies, R. M. et al. Study protocol: a double blind randomised control trial of high volume image guided injections in Achilles and patellar tendinopathy in a young active population. BMC Musculoskelet. Disord. 18, 204 (2017).

    PubMed  PubMed Central  Google Scholar 

  189. 189.

    Boesen, A. P., Hansen, R., Boesen, M. I., Malliaras, P. & Langberg, H. Effect of high-volume injection, platelet-rich plasma, and sham treatment in chronic midportion Achilles tendinopathy: a randomized double-blinded prospective study. Am. J. Sports Med. 45, 2034–2043 (2017).

    Google Scholar 

  190. 190.

    Korakakis, V., Whiteley, R., Tzavara, A. & Malliaropoulos, N. The effectiveness of extracorporeal shockwave therapy in common lower limb conditions: a systematic review including quantification of patient-rated pain reduction. Br. J. Sports Med. 52, 387–407 (2018).

    Google Scholar 

  191. 191.

    Mani-Babu, S., Morrissey, D., Waugh, C., Screen, H. & Barton, C. The effectiveness of extracorporeal shock wave therapy in lower limb tendinopathy: a systematic review. Am. J. Sports Med. 43, 752–761 (2015).

    Google Scholar 

  192. 192.

    Rompe, J. D. & Maffulli, N. Repetitive shock wave therapy for lateral elbow tendinopathy (tennis elbow): a systematic and qualitative analysis. Br. Med. Bull. 83, 355–378 (2007).

    Google Scholar 

  193. 193.

    Yan, C. et al. A comparative study of the efficacy of ultrasonics and extracorporeal shock wave in the treatment of tennis elbow: a meta-analysis of randomized controlled trials. J. Orthop. Surg. Res. 14, 248 (2019).

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    van den Boom, N. A. C., Winters, M., Haisma, H. J. & Moen, M. H. Efficacy of stem cell therapy for tendon disorders: a systematic review. Orthop. J. Sports Med. 8, 2325967120915857 (2020).

    PubMed  PubMed Central  Google Scholar 

  195. 195.

    Usuelli, F. G. et al. Intratendinous adipose-derived stromal vascular fraction (SVF) injection provides a safe, efficacious treatment for Achilles tendinopathy: results of a randomized controlled clinical trial at a 6-month follow-up. Knee Surg. Sports Traumatol. Arthrosc. 26, 2000–2010 (2018).

    Google Scholar 

  196. 196.

    Hunt, K. J., Cohen, B. E., Davis, W. H., Anderson, R. B. & Jones, C. P. Surgical treatment of insertional achilles tendinopathy with or without flexor hallucis longus tendon transfer: a prospective, randomized study. Foot Ankle Int. 36, 998–1005 (2015).

    Google Scholar 

  197. 197.

    Morrison, R. J. M., Brock, T. M., Reed, M. R. & Muller, S. D. Radiofrequency microdebridement versus surgical decompression for achilles tendinosis: a randomized controlled trial. J. Foot Ankle Surg. 56, 708–712 (2017).

    PubMed  PubMed Central  Google Scholar 

  198. 198.

    Bahr, R., Fossan, B., Loken, S. & Engebretsen, L. Surgical treatment compared with eccentric training for patellar tendinopathy (jumper’s knee). A randomized, controlled trial. J. Bone Joint Surg. Am. 88, 1689–1698 (2006).

    PubMed  PubMed Central  Google Scholar 

  199. 199.

    Willberg, L., Sunding, K., Forssblad, M., Fahlstrom, M. & Alfredson, H. Sclerosing polidocanol injections or arthroscopic shaving to treat patellar tendinopathy/jumper’s knee? A randomised controlled study. Br. J. Sports Med. 45, 411–415 (2011).

    PubMed  PubMed Central  Google Scholar 

  200. 200.

    Paavola, M. et al. Subacromial decompression versus diagnostic arthroscopy for shoulder impingement: randomised, placebo surgery controlled clinical trial. BMJ 362, k2860 (2018).

    PubMed  PubMed Central  Google Scholar 

  201. 201.

    Leppilahti, J., Raatikainen, T., Pienimaki, T., Hanninen, A. & Jalovaara, P. Surgical treatment of resistant tennis elbow. A prospective, randomised study comparing decompression of the posterior interosseous nerve and lengthening of the tendon of the extensor carpi radialis brevis muscle. Arch. Orthop. Trauma. Surg. 121, 329–332 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Tsolias, A., Detrembleur, C., Druez, V., Lequint, T. & Lefebvre, B. Effect of radial nerve release on lateral epicondylitis outcomes: a prospective, randomized, double-blinded trial. J. Hand Surg. Am. 44, 216–221 (2018).

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Clark, T. et al. Arthroscopic versus open lateral release for the treatment of lateral epicondylitis: a prospective randomized controlled trial. Arthroscopy 34, 3177–3184 (2018).

    PubMed  PubMed Central  Google Scholar 

  204. 204.

    Merolla, G. et al. Arthroscopic debridement versus platelet-rich plasma injection: a prospective, randomized, comparative study of chronic lateral epicondylitis with a nearly 2-year follow-up. Arthroscopy 33, 1320–1329 (2017).

    PubMed  PubMed Central  Google Scholar 

  205. 205.

    Kroslak, M. & Murrell, G. A. C. Surgical treatment of lateral epicondylitis: a prospective, randomized, double-blinded, placebo-controlled clinical trial. Am. J. Sports Med. 46, 1106–1113 (2018).

    PubMed  PubMed Central  Google Scholar 

  206. 206.

    Clement, N. D., Watts, A. C., Phillips, C. & McBirnie, J. M. Short-term outcome after arthroscopic bursectomy debridement of rotator cuff calcific tendonopathy with and without subacromial decompression: a prospective randomized controlled trial. Arthroscopy 31, 1680–1687 (2015).

    PubMed  PubMed Central  Google Scholar 

  207. 207.

    Lu, Y., Zhang, Q., Zhu, Y. & Jiang, C. Is radiofrequency treatment effective for shoulder impingement syndrome? A prospective randomized controlled study. J. Shoulder Elb. Surg. 22, 1488–1494 (2013).

    Google Scholar 

  208. 208.

    Haahr, J. P. et al. Exercises versus arthroscopic decompression in patients with subacromial impingement: a randomised, controlled study in 90 cases with a one year follow up. Ann. Rheum. Dis. 64, 760–764 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209.

    Haahr, J. P. & Andersen, J. H. Exercises may be as efficient as subacromial decompression in patients with subacromial stage II impingement: 4-8-years’ follow-up in a prospective, randomized study. Scand. J. Rheumatol. 35, 224–228 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210.

    Ketola, S., Lehtinen, J. T. & Arnala, I. Arthroscopic decompression not recommended in the treatment of rotator cuff tendinopathy: a final review of a randomised controlled trial at a minimum follow-up of ten years. Bone Joint J. 99-B, 799–805 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Beard, D. J. et al. Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial. Lancet 391, 329–338 (2018). This paper describes a pivotal randomized clinical trial on rotator cuff tendinopathy surgery.

    PubMed  PubMed Central  Google Scholar 

  212. 212.

    Challoumas, D., Clifford, C., Kirwan, P. & Millar, N. L. How does surgery compare to sham surgery or physiotherapy as a treatment for tendinopathy? A systematic review of randomised trials. BMJ Open Sport. Exerc. Med. 5, e000528 (2019).

    PubMed  PubMed Central  Google Scholar 

  213. 213.

    Fearon, A. M. et al. Greater trochanteric pain syndrome negatively affects work, physical activity and quality of life: a case control study. J. Arthroplasty 29, 383–386 (2014).

    PubMed  PubMed Central  Google Scholar 

  214. 214.

    Picavet, H. S. & Hoeymans, N. Health related quality of life in multiple musculoskeletal diseases: SF-36 and EQ-5D in the DMC3 study. Ann. Rheum. Dis. 63, 723–729 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215.

    Mc Auliffe, S. et al. Beyond the tendon: experiences and perceptions of people with persistent Achilles tendinopathy. Musculoskelet. Sci. Pract. 29, 108–114 (2017).

    Google Scholar 

  216. 216.

    Linton, S. J. & Shaw, W. S. Impact of psychological factors in the experience of pain. Phys. Ther. 91, 700–711 (2011).

    PubMed  PubMed Central  Google Scholar 

  217. 217.

    Celiker, R., Borman, P., Oktem, F., Gokce-Kutsal, Y. & Basgoze, O. Psychological disturbance in fibromyalgia: relation to pain severity. Clin. Rheumatol. 16, 179–184 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218.

    de Heer, E. W. et al. The association of depression and anxiety with pain: a study from NESDA. PLoS ONE 9, e106907 (2014).

    PubMed  PubMed Central  Google Scholar 

  219. 219.

    De Vries, A. J. et al. The impact of patellar tendinopathy on sports and work performance in active athletes. Res. Sports Med. 25, 253–265 (2017).

    PubMed  PubMed Central  Google Scholar 

  220. 220.

    Brinks, A. et al. Corticosteroid injections for greater trochanteric pain syndrome: a randomized controlled trial in primary care. Ann. Fam. Med. 9, 226–234 (2011).

    PubMed  PubMed Central  Google Scholar 

  221. 221.

    Alizadehkhaiyat, O., Fisher, A. C., Kemp, G. J., Vishwanathan, K. & Frostick, S. P. Upper limb muscle imbalance in tennis elbow: a functional and electromyographic assessment. J. Orthop. Res. 25, 1651–1657 (2007).

    PubMed  PubMed Central  Google Scholar 

  222. 222.

    MacDermid, J. C., Ramos, J., Drosdowech, D., Faber, K. & Patterson, S. The impact of rotator cuff pathology on isometric and isokinetic strength, function, and quality of life. J. Shoulder Elb. Surg. 13, 593–598 (2004).

    Google Scholar 

  223. 223.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03229291 (2017).

  224. 224.

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03344640 (2020).

  225. 225.

    Costa-Almeida, R., Calejo, I. & Gomes, M. E. Mesenchymal stem cells empowering tendon regenerative therapies. Int. J. Mol. Sci. 20, 3002 (2019).

    CAS  Google Scholar 

  226. 226.

    Pas, H., Moen, M. H., Haisma, H. J. & Winters, M. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br. J. Sports Med. 51, 996–1002 (2017).

    PubMed  PubMed Central  Google Scholar 

  227. 227.

    Nixon, A. J., Watts, A. E. & Schnabel, L. V. Cell- and gene-based approaches to tendon regeneration. J. Shoulder Elb. Surg. 21, 278–294 (2012).

    Google Scholar 

  228. 228.

    Longo, U. G., Lamberti, A., Maffulli, N. & Denaro, V. Tissue engineered biological augmentation for tendon healing: a systematic review. Br. Med. Bull. 98, 31–59 (2011).

    PubMed  PubMed Central  Google Scholar 

  229. 229.

    Youngstrom, D. W. & Barrett, J. G. Engineering tendon: scaffolds, bioreactors, and models of regeneration. Stem Cell Int. 2016, 3919030 (2016).

    Google Scholar 

  230. 230.

    Gonzalez-Quevedo, D., Martinez-Medina, I., Campos, A., Campos, F. & Carriel, V. Tissue engineering strategies for the treatment of tendon injuries: a systematic review and meta-analysis of animal models. Bone Joint Res. 7, 318–324 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231.

    Parchi, P. D. et al. Nanoparticles for tendon healing and regeneration: literature review. Front. Aging Neurosci. 8, 202 (2016).

    PubMed  PubMed Central  Google Scholar 

  232. 232.

    Ruergard, A., Spang, C. & Alfredson, H. Results of minimally invasive Achilles tendon scraping and plantaris tendon removal in patients with chronic midportion Achilles tendinopathy: a longer-term follow-up study. SAGE Open Med. 7, 2050312118822642 (2019).

    PubMed  PubMed Central  Google Scholar 

  233. 233.

    Millar, N. L., Murrell, G. A. C. & Kirwan, P. Time to put down the scalpel? The role of surgery in tendinopathy. Br. J. Sports Med. 54, 441–442 (2020). This paper discusses the role of surgery in tendinopathy.

    Google Scholar 

  234. 234.

    Rio, E. K. et al. ICON PART-T 2019–International Scientific Tendinopathy Symposium Consensus: recommended standards for reporting participant characteristics in tendinopathy research (PART-T). Br. J. Sports Med. 54, 627–630 (2020).

    Google Scholar 

  235. 235.

    Vicenzino, B. et al. ICON 2019–International Scientific Tendinopathy Symposium Consensus: There are nine core health-related domains for tendinopathy (CORE DOMAINS): Delphi study of healthcare professionals and patients. Br. J. Sports Med. 54, 444–451 (2020).

    Google Scholar 

  236. 236.

    Malliaras, P., Cook, J., Purdam, C. & Rio, E. Patellar tendinopathy: clinical diagnosis, load management, and advice for challenging case presentations. J. Orthop. Sports Phys. Ther. 45, 887–898 (2015).

    Google Scholar 

  237. 237.

    Maffulli, N. et al. The Royal London Hospital Test for the clinical diagnosis of patellar tendinopathy. Muscles Ligaments Tendons J. 7, 315–322 (2017).

    PubMed  PubMed Central  Google Scholar 

  238. 238.

    Taylor, S. A. & Hannafin, J. A. Evaluation and management of elbow tendinopathy. Sports Health 4, 384–393 (2012).

    PubMed  PubMed Central  Google Scholar 

  239. 239.

    Lewis, J., McCreesh, K., Roy, J. S. & Ginn, K. Rotator cuff tendinopathy: navigating the diagnosis–management conundrum. J. Orthop. Sports Phys. Ther. 45, 923–937 (2015).

    Google Scholar 

  240. 240.

    Burry, H. C. Pathogenesis of some traumatic and degenerative disorders of soft tissue. Aust N. Z. J. Med. 8 (Suppl. 1), 163–167 (1978).

    Google Scholar 

  241. 241.

    Leadbetter, W. B. Cell-matrix response in tendon injury. Clin. Sports Med. 11, 533–578 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. 242.

    Khan, K. M., Cook, J. L., Bonar, F., Harcourt, P. & Astrom, M. Histopathology of common tendinopathies. Update and implications for clinical management. Sports Med. 27, 393–408 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. 243.

    Wang, J. H. et al. Cyclic mechanical stretching of human tendon fibroblasts increases the production of prostaglandin E2 and levels of cyclooxygenase expression: a novel in vitro model study. Connect. Tissue Res. 44, 128–133 (2003).

    CAS  Google Scholar 

  244. 244.

    Almekinders, L. C., Weinhold, P. S. & Maffulli, N. Compression etiology in tendinopathy. Clin. Sports Med. 22, 703–710 (2003).

    Google Scholar 

  245. 245.

    Puddu, G., Ippolito, E. & Postacchini, F. A classification of Achilles tendon disease. Am. J. Sports Med. 4, 145–150 (1976).

    CAS  Google Scholar 

  246. 246.

    Abate, M. et al. Pathogenesis of tendinopathies: inflammation or degeneration? Arthritis Res. Ther. 11, 235 (2009).

    PubMed  PubMed Central  Google Scholar 

  247. 247.

    Rees, J. D., Stride, M. & Scott, A. Tendons–time to revisit inflammation. Br. J. Sports Med. 48, 1553–1557 (2014).

    Google Scholar 

  248. 248.

    Pufe, T., Petersen, W. J., Mentlein, R. & Tillmann, B. N. The role of vasculature and angiogenesis for the pathogenesis of degenerative tendons disease. Scand. J. Med. Sci. Sports 15, 211–222 (2005).

    CAS  Google Scholar 

  249. 249.

    Fredberg, U. & Stengaard-Pedersen, K. Chronic tendinopathy tissue pathology, pain mechanisms, and etiology with a special focus on inflammation. Scand. J. Med. Sci. Sports 18, 3–15 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 250.

    Cook, J. L., Rio, E., Purdam, C. R. & Docking, S. I. Revisiting the continuum model of tendon pathology: what is its merit in clinical practice and research? Br. J. Sports Med. 50, 1187–1191 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. 251.

    Cook, J. L. & Purdam, C. R. Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy. Br. J. Sports Med. 43, 409–416 (2009).

    CAS  Google Scholar 

  252. 252.

    Fu, S. C., Rolf, C., Cheuk, Y. C., Lui, P. P. & Chan, K. M. Deciphering the pathogenesis of tendinopathy: a three-stages process. Sports Med. Arthrosc. Rehabil. Ther. Technol. 2, 30 (2010).

    PubMed  PubMed Central  Google Scholar 

  253. 253.

    Visnes H. et al. No effect of eccentric training on jumper’s knee in volleyball players during the competitive season: a randomized clinical trial. Clin. J. Sport Med. 15, 227–234 (2005).

    PubMed  PubMed Central  Google Scholar 

  254. 254.

    Andersen L. L. et al. Effect of specific resistance training on forearm pain and work disability in industrial technicians: cluster randomised controlled trial. BMJ Open 2, e000412 (2012).

    PubMed  PubMed Central  Google Scholar 

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Contributions

Introduction (N.L.M., G.A.C.M. and I.B.M.); Epidemiology (N.L.M., K.G.S. and K.T.); Mechanisms/pathophysiology (N.L.M., G.D.A., P.D.K., S.A.R. and L.M.G.); Diagnosis, screening and prevention (N.L.M., P.D.K., S.A.R., K.G.S. and K.T.); Management (N.L.M., G.D.A., P.D.K., G.A.C.M., K.G.S., K.T. and L.M.G.); Quality of life (N.L.M. and P.D.K.); Outlook (N.L.M., G.D.A. and I.B.M.); Overview of Primer (N.L.M.).

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Correspondence to Neal L. Millar.

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Nature Reviews Disease Primers thanks M. Kjaer, N. Maffulli and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Rotator cuff impingement

Previously used term to describe rotator cuff tendinopathy, that is, pain and weakness, most commonly experienced with movements of shoulder external rotation and elevation, as a consequence of excessive load on the rotator cuff tissue.

Subacromial pain syndrome

Pain, weakness and loss of function of the shoulder usually resulting from overhead activities.

Plantar fascia

Thick, web-like ligament that connects the heel to the front of the foot. This ligament acts as a shock absorber and supports the arch of the foot, facilitating walking.

Achilles tendon

A strong fibrous cord that connects the muscles in the back of the calf to the calcaneus bone.

Greater trochanter

The attachment site for five muscles: the gluteus medius, gluteus minimus, piriformis, obturator externus and obturator internus.

Patellar tendon

The tendon running inferiorly from the patella bone to the tibial tuberosity.

Tibialis posterior tendon

The tendon on the inner side of the ankle that assists in maintaining the arch of the foot as well as the ability to turn the ankle inwards.

Tensile load

The ability of a material to withstand a pulling force.

Interfascicular matrix

The endotenon that facilitates sliding between fascicles

Fatigue resistance

Resistance to the weakening of a material caused by cyclic loading.

Resolution pathways

Programmed responses activated during inflammation resulting in a switch of lipid mediators that leads to resolution of inflammation.

Bursitis

Inflammation or irritation of a bursa sac.

Eccentric training

An eccentric contraction is the motion of an active muscle while it is lengthening under load. Eccentric training is repetitively doing eccentric muscle contractions.

Pain monitoring model

Physiotherapy model showing that one can safely continue some activity in a patient with Achilles tendinopathy by monitoring patient pain.

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Millar, N.L., Silbernagel, K.G., Thorborg, K. et al. Tendinopathy. Nat Rev Dis Primers 7, 1 (2021). https://doi.org/10.1038/s41572-020-00234-1

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