Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The pathogenesis of tendinopathy: balancing the response to loading

This article has been updated

Abstract

Tendons are designed to withstand considerable loads. Mechanical loading of tendon tissue results in upregulation of collagen expression and increased synthesis of collagen protein, the extent of which is probably regulated by the strain experienced by the resident fibroblasts (tenocytes). This increase in collagen formation peaks around 24 h after exercise and remains elevated for about 3 days. The degradation of collagen proteins also rises after exercise, but seems to peak earlier than the synthesis. Despite the ability of tendons to adapt to loading, repetitive use often results in injuries, such as tendinopathy, which is characterized by pain during activity, localized tenderness upon palpation, swelling and impaired performance. Tendon histological changes include reduced numbers and rounding of fibroblasts, increased content of proteoglycans, glycosaminoglycans and water, hypervascularization and disorganized collagen fibrils. At the molecular level, the levels of messenger RNA for type I and III collagens, proteoglycans, angiogenic factors, stress and regenerative proteins and proteolytic enzymes are increased. Tendon microrupture and material fatigue have been suggested as possible injury mechanisms, thus implying that one or more 'weak links' are present in the structure. Understanding how tendon tissue adapts to mechanical loading will help to unravel the pathogenesis of tendinopathy.

Key Points

  • Tendons are metabolically active and respond readily to both loading and unloading

  • Mechanical loading results both in protein synthesis and degradation of collagen

  • Without sufficient rest (24 h) after exercise, net loss of collagen might occur that leaves the tendon vulnerable to injury

  • Tendinopathy is associated with neovascularization, but newly formed blood vessels (and nerves) disappear during healing

  • The pathogenesis of tendinopathy can be accelerated by overloading

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The different hierarchical levels (tendon–molecule) of the human Achilles tendon.
Figure 2: Schematic representation of collagen synthesis and degradation.
Figure 3: Response of collagen to loading.

Change history

  • 09 April 2010

    In the version of this article initially published online, the tendon in Figure 1 was indicated as being 0.5–1.0mm2 instead of 0.5–1.0cm2. In addition, the measurements relating to the collagen fascicle, fibril and molecule in Figure 1 should all refer to the diameter of these entities. These errors have been corrected in all versions of the article.

References

  1. 1

    Finni, T., Komi, P. V. & Lepola, V. In vivo human triceps surae and quadriceps femoris muscle function in a squat jump and counter movement jump. Eur. J. Appl. Physiol. 83, 416–426 (2000).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Giddings, V. L., Beaupre, G. S., Whalen, R. T. & Carter, D. R. Calcaneal loading during walking and running. Med. Sci. Sports Exerc. 32, 627–634 (2000).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Magnusson, S. P., Aagaard, P., Dyhre-Poulsen, P. & Kjaer, M. Load-displacement properties of the human triceps surae aponeurosis in vivo. J. Physiol. 531, 277–288 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Khan, K. & Cook, J. The painful nonruptured tendon: clinical aspects. Clin. Sports Med. 22, 711–725 (2003).

    PubMed  Article  Google Scholar 

  5. 5

    Maffulli, N., Khan, K. M. & Puddu, G. Overuse tendon conditions: time to change a confusing terminology. Arthroscopy 14, 840–843 (1998).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Ferretti, A. Epidemiology of jumper's knee. Sports Med. 3, 289–295 (1986).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Frost, P. et al. Risk of shoulder tendinitis in relation to shoulder loads in monotonous repetitive work. Am. J. Ind. Med. 41, 11–18 (2002).

    PubMed  Article  Google Scholar 

  8. 8

    Tanaka, S., Petersen, M. & Cameron, L. Prevalence and risk factors of tendinitis and related disorders of the distal upper extremity among U. S. workers: comparison to carpal tunnel syndrome. Am. J. Ind. Med. 39, 328–335 (2001).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Gruchow, H. W. & Pelletier, D. An epidemiologic study of tennis elbow. Incidence, recurrence, and effectiveness of prevention strategies. Am. J. Sports Med. 7, 234–238 (1979).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Lian, O. B., Engebretsen, L. & Bahr, R. Prevalence of jumper's knee among elite athletes from different sports: a cross-sectional study. Am. J. Sports Med. 33, 561–567 (2005).

    PubMed  Article  Google Scholar 

  11. 11

    Knobloch, K., Yoon, U. & Vogt, P. M. Acute and overuse injuries correlated to hours of training in master running athletes. Foot Ankle Int. 29, 671–676 (2008).

    PubMed  Article  Google Scholar 

  12. 12

    Kettunen, J. A., Kvist, M., Alanen, E. & Kujala, U. M. Long-term prognosis for jumper's knee in male athletes. A prospective follow-up study. Am. J. Sports Med. 30, 689–692 (2002).

    PubMed  Article  Google Scholar 

  13. 13

    Bojsen-Moller, J., Kalliokoski, K. K., Seppanen, M., Kjaer, M. & Magnusson, S. P. Low-intensity tensile loading increases intratendinous glucose uptake in the Achilles tendon. J. Appl. Physiol. 101, 196–201 (2006).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Langberg, H., Rosendal, L. & Kjaer, M. Training-induced changes in peritendinous type I collagen turnover determined by microdialysis in humans. J. Physiol. 534, 297–302 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Ker, R. F., Alexander, R. M. & Bennett, M. B. Why are mammalian tendons so thick? J. Zoo. Lond. 216, 309–324 (1988).

    Article  Google Scholar 

  16. 16

    Komi, P. V., Fukashiro, S. & Jarvinen, M. Biomechanical loading of Achilles tendon during normal locomotion. Clin. Sports Med. 11, 521–531 (1992).

    CAS  PubMed  Google Scholar 

  17. 17

    Nakama, L. H., King, K. B., Abrahamsson, S. & Rempel, D. M. Evidence of tendon microtears due to cyclical loading in an in vivo tendinopathy model. J. Orthop. Res. 23, 1199–1205 (2005).

    PubMed  Article  Google Scholar 

  18. 18

    Ker, R. F. The implications of the adaptable fatigue quality of tendons for their construction, repair and function. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 133, 987–1000 (2002).

    PubMed  Article  Google Scholar 

  19. 19

    Kastelic, J., Galeski, A. & Baer, E. The multicomposite structure of tendon. Connect. Tissue Res. 6, 11–23 (1978).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Kadler, K. E., Holmes, D. F., Trotter, J. A. & Chapman, J. A. Collagen fibril formation. Biochem. J. 316 (Pt 1), 1–11 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Bailey, A. J. Molecular mechanisms of ageing in connective tissues. Mech. Ageing Dev. 122, 735–755 (2001).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Barnard, K., Light, N. D., Sims, T. J. & Bailey, A. J. Chemistry of the collagen cross-links. Origin and partial characterization of a putative mature cross-link of collagen. Biochem. J. 244, 303–309 (1987).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Riley, G. P. Gene expression and matrix turnover in overused and damaged tendons. Scand. J. Med. Sci. Sports 15, 241–251 (2005).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Kjaer, M. Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. Physiol. Rev. 84, 649–698 (2004).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Haraldsson, B. T. et al. Region-specific mechanical properties of the human patella tendon. J. Appl. Physiol. 98, 1006–1012 (2005).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Haraldsson, B. T. et al. Lateral force transmission between human tendon fascicles. Matrix Biol. 27, 86–95 (2008).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Parry, D. A., Barnes, G. R. & Craig, A. S. A comparison of the size distribution of collagen fibrils in connective tissues as a function of age and a possible relation between fibril size distribution and mechanical properties. Proc. R. Soc. Lond. B Biol. Sci. 203, 305–321 (1978).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Lujan, T. J., Underwood, C. J., Jacobs, N. T. & Weiss, J. A. Contribution of glycosaminoglycans to viscoelastic tensile behavior of human ligament. J. Appl. Physiol. 106, 423–431 (2009).

    PubMed  Article  Google Scholar 

  29. 29

    Provenzano, P. P. & Vanderby, R. Jr. Collagen fibril morphology and organization: implications for force transmission in ligament and tendon. Matrix Biol. 25, 71–84 (2006).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Scott, J. E. Elasticity in extracellular matrix 'shape modules' of tendon, cartilage, etc. A sliding proteoglycan-filament model. J. Physiol. 553, 335–343 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Puxkandl, R. et al. Viscoelastic properties of collagen: synchrotron radiation investigations and structural model. Philos. Trans. R. Soc. Lond. B Biol. Sci. 357, 191–197 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Mosler, E. et al. Stress-induced molecular rearrangement in tendon collagen. J. Mol. Biol. 182, 589–596 (1985).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Dahners, L. E., Lester, G. E. & Caprise, P. The pentapeptide NKISK affects collagen fibril interactions in a vertebrate tissue. J. Orthop. Res. 18, 532–536 (2000).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Buehler, M. J. Nanomechanics of collagen fibrils under varying cross-link densities: atomistic and continuum studies. J. Mech. Behav. Biomed. Mater. 1, 59–67 (2008).

    PubMed  Article  Google Scholar 

  35. 35

    Fratzl, P. et al. Fibrillar structure and mechanical properties of collagen. J. Struct. Biol. 122, 119–122 (1998).

    CAS  Article  Google Scholar 

  36. 36

    Sasaki, N. & Odajima, S. Elongation mechanism of collagen fibrils and force-strain relations of tendon at each level of structural hierarchy. J. Biomech. 29, 1131–1136 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Sasaki, N. & Odajima, S. Stress-strain curve and Young's modulus of a collagen molecule as determined by the X-ray diffraction technique. J. Biomech. 29, 655–658 (1996).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Lorenzo, A. C. & Caffarena, E. R. Elastic properties, Young's modulus determination and structural stability of the tropocollagen molecule: a computational study by steered molecular dynamics. J. Biomech. 38, 1527–1533 (2005).

    PubMed  Article  Google Scholar 

  39. 39

    Screen, H. R., Lee, D. A., Bader, D. L. & Shelton, J. C. An investigation into the effects of the hierarchical structure of tendon fascicles on micromechanical properties. Proc. Inst. Mech. Eng. H 218, 109–119 (2004).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Arnoczky, S. P., Lavagnino, M., Whallon, J. H. & Hoonjan, A. In situ cell nucleus deformation in tendons under tensile load; a morphological analysis using confocal laser microscopy. J. Orthop. Res. 20, 29–35 (2002).

    PubMed  Article  Google Scholar 

  41. 41

    Arnoczky, S. P., Lavagnino, M. & Egerbacher, M. The mechanobiological aetiopathogenesis of tendinopathy: is it the over-stimulation or the under-stimulation of tendon cells? Int. J. Exp. Pathol. 88, 217–226 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Danielson, P., Andersson, G., Alfredson, H. & Forsgren, S. Extensive expression of markers for acetylcholine synthesis and of M2 receptors in tenocytes in therapy-resistant chronic painful patellar tendon tendinosis—a pilot study. Life Sci. 80, 2235–2238 (2007).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Riley, G. P., Goddard, M. J. & Hazleman, B. L. Histopathological assessment and pathological significance of matrix degeneration in supraspinatus tendons. Rheumatology (Oxford) 40, 229–230 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Lian, O. et al. Excessive apoptosis in patellar tendinopathy in athletes. Am. J. Sports Med. 35, 605–611 (2007).

    PubMed  Article  Google Scholar 

  45. 45

    Scott, A. et al. High strain mechanical loading rapidly induces tendon apoptosis: an ex vivo rat tibialis anterior model. Br. J. Sports Med. 39, e25 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    Wang, F., Murrell, G. A. & Wang, M. X. Oxidative stress-induced c-Jun N.-terminal kinase (JNK) activation in tendon cells upregulates MMP1 mRNA and protein expression. J. Orthop. Res. 25, 378–389 (2007).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    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  Article  Google Scholar 

  48. 48

    Corps, A. N. et al. The regulation of aggrecanase ADAMTS-4 expression in human Achilles tendon and tendon-derived cells. Matrix Biol. 27, 393–401 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Corps, A. N. et al. Versican splice variant messenger RNA expression in normal human Achilles tendon and tendinopathies. Rheumatology (Oxford) 43, 969–972 (2004).

    CAS  Article  Google Scholar 

  50. 50

    Jones, G. C. et al. Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon. Arthritis Rheum. 54, 832–842 (2006).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Corps, A. N. et al. Increased expression of aggrecan and biglycan mRNA in Achilles tendinopathy. Rheumatology (Oxford) 45, 291–294 (2006).

    CAS  Article  Google Scholar 

  52. 52

    Corps, A. N., Curry, V. A., Buttle, D. J., Hazleman, B. L. & Riley, G. P. Inhibition of interleukin-1β-stimulated collagenase and stromelysin expression in human tendon fibroblasts by epigallocatechin gallate ester. Matrix Biol. 23, 163–169 (2004).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Xu, Y. & Murrell, G. A. The basic science of tendinopathy. Clin. Orthop. Relat. Res. 466, 1528–1538 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Drummond, A. H. et al. Preclinical and clinical studies of MMP inhibitors in cancer. Ann. NY Acad. Sci. 878, 228–235 (1999).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Jones, L., Ghaneh, P., Humphreys, M. & Neoptolemos, J. P. The matrix metalloproteinases and their inhibitors in the treatment of pancreatic cancer. Ann. NY Acad. Sci. 880, 288–307 (1999).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Archambault, J. M. et al. Rat supraspinatus tendon expresses cartilage markers with overuse. J. Orthop. Res. 25, 617–624 (2007).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Goncalves-Neto, J. et al. Changes in collagen matrix composition in human posterior tibial tendon dysfunction. Joint Bone Spine 69, 189–194 (2002).

    PubMed  Article  Google Scholar 

  58. 58

    Riley, G. P. et al. Tendon degeneration and chronic shoulder pain: changes in the collagen composition of the human rotator cuff tendons in rotator cuff tendinitis. Ann. Rheum. Dis. 53, 359–366 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Bank, R. A., TeKoppele, J. M., Oostingh, G., Hazleman, B. L. & Riley, G. P. Lysylhydroxylation and non-reducible crosslinking of human supraspinatus tendon collagen: changes with age and in chronic rotator cuff tendinitis. Ann. Rheum. Dis. 58, 35–41 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

    de Mos, M. et al. Achilles tendinosis: changes in biochemical composition and collagen turnover rate. Am. J. Sports Med. 35, 1549–1556 (2007).

    PubMed  Article  Google Scholar 

  61. 61

    Riley, G. P., Harrall, R. L., Cawston, T. E., Hazleman, B. L. & Mackie, E. J. Tenascin-C and human tendon degeneration. Am. J. Pathol. 149, 933–943 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    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  Article  Google Scholar 

  63. 63

    Lejard, V. et al. Scleraxis and NFATc regulate the expression of the pro-alpha1(I) collagen gene in tendon fibroblasts. J. Biol. Chem. 282, 17665–17675 (2007).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Heinemeier, K. M. et al. Expression of collagen and related growth factors in rat tendon and skeletal muscle in response to specific contraction types. J. Physiol. 582, 1303–1316 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Miller, B. F. et al. Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise. J. Physiol. 567, 1021–1033 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Langberg, H., Skovgaard, D., Karamouzis, M., Bulow, J. & Kjaer, M. Metabolism and inflammatory mediators in the peritendinous space measured by microdialysis during intermittent isometric exercise in humans. J. Physiol. 515, 919–927 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67

    Koskinen, S. O., Heinemeier, K. M., Olesen, J. L., Langberg, H. & Kjaer, M. Physical exercise can influence local levels of matrix metalloproteinases and their inhibitors in tendon-related connective tissue. J. Appl. Physiol. 96, 861–864 (2004).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Couppe, C. et al. Habitual loading results in tendon hypertrophy and increased stiffness of the human patellar tendon. J. Appl. Physiol. 105, 805–810 (2008).

    CAS  PubMed  Article  Google Scholar 

  69. 69

    Kovanen, V. Effects of ageing and physical training on rat skeletal muscle. An experimental study on the properties of collagen, laminin, and fibre types in muscles serving different functions. Acta Physiol. Scand. Suppl. 577, 1–56 (1989).

    CAS  PubMed  Google Scholar 

  70. 70

    de Boer, M. D. et al. The temporal responses of protein synthesis, gene expression and cell signalling in human quadriceps muscle and patellar tendon to disuse. J. Physiol. 585, 241–251 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Mokone, G. G. et al. The guanine-thymine dinucleotide repeat polymorphism within the tenascin-C gene is associated with achilles tendon injuries. Am. J. Sports Med. 33, 1016–1021 (2005).

    PubMed  Article  Google Scholar 

  72. 72

    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  Article  Google Scholar 

  73. 73

    Rees, S. G., Dent, C. M. & Caterson, B. Metabolism of proteoglycans in tendon. Scand. J. Med. Sci. Sports 19, 470–478 (2009).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Samiric, T., Ilic, M. Z. & Handley, C. J. Large aggregating and small leucine-rich proteoglycans are degraded by different pathways and at different rates in tendon. Eur. J. Biochem. 271, 3612–3620 (2004).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Jepsen, K. J. et al. A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice. J. Biol. Chem. 277, 35532–35540 (2002).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Iozzo, R. V. The biology of the small leucine-rich proteoglycans. Functional network of interactive proteins. J. Biol. Chem. 274, 18843–18846 (1999).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Rees, S. G., Waggett, A. D., Dent, C. M. & Caterson, B. Inhibition of aggrecan turnover in short-term explant cultures of bovine tendon. Matrix Biol. 26, 280–290 (2007).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Olesen, J. L. et al. Expression, content, and localization of insulin-like growth factor I in human achilles tendon. Connect. Tissue Res. 47, 200–206 (2006).

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Kjaer, M. et al. From mechanical loading to collagen synthesis, structural changes and function in human tendon. Scand. J. Med. Sci. Sports 19, 500–510 (2009).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    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  Article  Google Scholar 

  81. 81

    Abrahamsson, S. O. Similar effects of recombinant human insulin-like growth factor-I and II on cellular activities in flexor tendons of young rabbits: experimental studies in vitro. J. Orthop. Res. 15, 256–262 (1997).

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Schild, C. & Trueb, B. Mechanical stress is required for high-level expression of connective tissue growth factor. Exp. Cell Res. 274, 83–91 (2002).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Yang, G., Crawford, R. C. & Wang, J. H. Proliferation and collagen production of human patellar tendon fibroblasts in response to cyclic uniaxial stretching in serum-free conditions. J. Biomech. 37, 1543–1550 (2004).

    PubMed  Article  Google Scholar 

  84. 84

    Heinemeier, K. M. et al. Effect of unloading followed by reloading on expression of collagen and related growth factors in rat tendon and muscle. J. Appl. Physiol. 106, 178–186 (2009).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Sakata, T. et al. Skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways. J. Bone Miner. Res. 19, 436–446 (2004).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Yu, W. D., Panossian, V., Hatch, J. D., Liu, S. H. & Finerman, G. A. Combined effects of estrogen and progesterone on the anterior cruciate ligament. Clin. Orthop. Relat. Res. 383, 268–281 (2001).

    Article  Google Scholar 

  87. 87

    Miller, B. F. et al. Tendon collagen synthesis at rest and after exercise in women. J. Appl. Physiol. 102, 541–546 (2007).

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Miller, B. F. et al. No effect of menstrual cycle on myofibrillar and connective tissue protein synthesis in contracting skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 290, E163–E168 (2006).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Hansen, M. et al. Effect of administration of oral contraceptives in vivo on collagen synthesis in tendon and muscle connective tissue in young women. J. Appl. Physiol. 106, 1435–1443 (2009).

    CAS  PubMed  Article  Google Scholar 

  90. 90

    Westh, E. et al. Effect of habitual exercise on the structural and mechanical properties of human tendon, in vivo, in men and women. Scand. J. Med. Sci. Sports 18, 23–30 (2008).

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Hewett, T. E., Myer, G. D. & Ford, K. R. Anterior cruciate ligament injuries in female athletes: Part 1, mechanisms and risk factors. Am. J. Sports Med. 34, 299–311 (2006).

    PubMed  Article  Google Scholar 

  92. 92

    Trappe, T. A. et al. Effect of ibuprofen and acetaminophen on postexercise muscle protein synthesis. Am. J. Physiol. Endocrinol. Metab. 282, E551–E556 (2002).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Mackey, A. L. et al. The influence of anti-inflammatory medication on exercise-induced myogenic precursor cell responses in humans. J. Appl. Physiol. 103, 425–431 (2007).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    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  Article  Google Scholar 

  95. 95

    Schatzker, J. & Branemark, P. I. Intravital observations on the microvascular anatomy and microcirculation of the tendon. Acta Orthop. Scand. Suppl. 126, 1–23 (1969).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Astrom, M. & Westlin, N. Blood flow in the human Achilles tendon assessed by laser Doppler flowmetry. J. Orthop. Res. 12, 246–252 (1994).

    CAS  PubMed  Article  Google Scholar 

  97. 97

    Boushel, R. et al. Blood flow and oxygenation in peritendinous tissue and calf muscle during dynamic exercise in humans. J. Physiol. 524 (Pt 1), 305–313 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    de Vos, R. J., Weir, A., Cobben, L. P. & Tol, J. L. The value of power Doppler ultrasonography in Achilles tendinopathy: a prospective study. Am. J. Sports Med. 35, 1696–1701 (2007).

    PubMed  Article  Google Scholar 

  99. 99

    Astrom, M. & Westlin, N. Blood flow in chronic Achilles tendinopathy. Clin. Orthop. Relat. Res. 308, 166–172 (1994).

    Google Scholar 

  100. 100

    Ohberg, L. & Alfredson, H. Effects on neovascularisation behind the good results with eccentric training in chronic mid-portion Achilles tendinosis? Knee Surg. Sports Traumatol. Arthrosc. 12, 465–470 (2004).

    PubMed  Article  Google Scholar 

  101. 101

    Hoksrud, A., Ohberg, L., Alfredson, H. & Bahr, R. Color Doppler ultrasound findings in patellar tendinopathy (jumper's knee). Am. J. Sports Med. 36, 1813–1820 (2008).

    PubMed  Article  Google Scholar 

  102. 102

    Ackermann, P. W., Salo, P. T. & Hart, D. A. Neuronal pathways in tendon healing. Front. Biosci. 14, 5165–5187 (2009).

    CAS  Google Scholar 

  103. 103

    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  PubMed  Article  Google Scholar 

  104. 104

    Ackermann, P. W., Finn, A. & Ahmed, M. Sensory neuropeptidergic pattern in tendon, ligament and joint capsule. A study in the rat. Neuroreport 10, 2055–2060 (1999).

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Ackermann, P. W., Li, J., Finn, A., Ahmed, M. & Kreicbergs, A. Autonomic innervation of tendons, ligaments and joint capsules. A morphologic and quantitative study in the rat. J. Orthop. Res. 19, 372–378 (2001).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Bring, D. K., Kreicbergs, A., Renstrom, P. A. & Ackermann, P. W. Physical activity modulates nerve plasticity and stimulates repair after Achilles tendon rupture. J. Orthop. Res. 25, 164–172 (2007).

    PubMed  Article  Google Scholar 

  107. 107

    Bring, D. K. et al. Joint immobilization reduces the expression of sensory neuropeptide receptors and impairs healing after tendon rupture in a rat model. J. Orthop. Res. 27, 274–280 (2009).

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Glazebrook, M. A., Wright, J. R., Jr, Langman, M., Stanish, W. D. & Lee, J. M. Histological analysis of achilles tendons in an overuse rat model. J. Orthop. Res. 26, 840–846 (2008).

    PubMed  Article  Google Scholar 

  109. 109

    September, A. V., Schwellnus, M. P. & Collins, M. Tendon and ligament injuries: the genetic component. Br. J. Sports Med. 41, 241–246 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  110. 110

    Collins, M. & Raleigh, S. M. Genetic risk factors for musculoskeletal soft tissue injuries. Med. Sport Sci. 54, 136–149 (2009).

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Langberg, H., Skovgaard, D., Petersen, L. J., Bulow, J. & Kjaer, M. Type I collagen synthesis and degradation in peritendinous tissue after exercise determined by microdialysis in humans. J. Physiol. 521 (Pt 1), 299–306 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael Kjaer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Magnusson, S., Langberg, H. & Kjaer, M. The pathogenesis of tendinopathy: balancing the response to loading. Nat Rev Rheumatol 6, 262–268 (2010). https://doi.org/10.1038/nrrheum.2010.43

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing