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The pathogenesis of tendinopathy: balancing the response to loadingS. Peter Magnusson, Henning Langberg and Michael Kjaer 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.
Magnusson, S. P. et al. Nat. Rev. Rheumatol. 6, 262–268 (2010); published online 23 March Tendon tissue has an essential role in transmitting exerted on a tendon will depend on its cross-sectional contractile forces to bone to generate movement, and area. Human tendons, including the commonly afflicted is therefore uniquely designed to withstand consider- patellar and Achilles tendons, typically have a fracture able loads (up to 8 times body weight) during human stress of 100 MPa. However, most tendons are only sub- locomotion.1–3 However, repetitive loading often results jected to stresses of up to 30 MPa,15 which gives tendons in overuse injuries, such as tendinopathy, which is a a reasonable safety margin, although the Achilles tendon common clinical condition characterized by pain during might experience stresses of up to 70 MPa.1,16 Tendon activity, localized tenderness upon palpation, swelling of microrupture, which is presumably associated with a lack the tendon and impaired performance.4,5 Tendinopathy is of load in a local area along with its associated fibroblasts, a problem in both elite and recreational athletes, as well as has been suggested as a possible injury mechanism for in the workplace.6–8 In some elite athletes, the prevalence tendinopathy.6,17 It has also been suggested that fatigue, can be as high as 45%,6,9–11 and the symptoms, as well defined as the time-dependent damage that occurs in as any reduction in performance, might be long lasting response to cyclic loading, might be an injury mechanism (many years, in some cases).12 The injury mechanism is in tendon.18 The precise mechanism of injury that leads to currently poorly understood. Human tendons have tradi- tendinopathy remains unknown, but the proposed mecha- tional y been considered largely inert structures, but are nisms imply that there are one or more ‘weak links' in the now known to be metabolical y active in their response to tendon structure that result in the pathological response mechanical loading.13,14 Understanding how tendon tissue of the fibroblast.
adapts to mechanical loading is key to understanding the Institute of Sports patho genesis of tendino pathy, and will thus provide Structure of tendon tissue Medicine, Bispebjerg Hospital and Center for the basis for preventing these overuse injuries. In this The organization of tendon follows a strict hierarchi- Healthy Aging, Faculty Review, we discuss current knowledge of how the various cal pattern (Figure 1).19 Collagen molecules are orga- of Health Sciences, Bispebjerg Hospital, components of the human tendon respond to acute and nized precisely to give rise to the characteristic 67 nm Building 8, University of chronic loading.
and aggregated molecules of the fibril are stabilized by The average tensile stress (which relates to the force covalent intermolecular crosslinks.21,22 The crosslinks (S. P. Magnusson, H. Langberg, M. Kjaer).
transmitted and the area over which it is transmitted) bind the col a gen molecules to one another and thereby confer integrity on the fibril. Groups of fibrils then form Correspondence to: Competing interests fibers known as fascicle bundles, which final y co mprise The authors declare no competing interests.
col agen.23 The fibril ar col agen is embedded in a hydro- philic extra cel ular matrix consisting of proteo glycans, ■ Tendons are metabolically active and respond readily to both loading glycoproteins and glyco saminoglycans, which are involved in the develop ment, organization and growth ■ Mechanical loading results both in protein synthesis and degradation of collagen control of tendon.24 ■ without sufficient rest (24 h) after exercise, net loss of collagen might occur that leaves the tendon vulnerable to injury Force transmission within the tendon ■ Tendinopathy is associated with neovascularization, but newly formed blood The tendon might be functional y regarded as a single vessels (and nerves) disappear during healing force-transmitting structure, but it remains unknown ■ The pathogenesis of tendinopathy can be accelerated by overloading if force is transmitted evenly throughout the tendon, and therefore whether the stress–strain on tendons is homo- geneous. whether there is a ‘weak link' in the force trans- Tendon, 0.5–1.0 cm2 mission and how it might adapt to loading conditions remain enigmatic issues.
Fascicles from the anterior and posterior portion of the human patellar tendon display substantially dif- ferent mechanical properties.25 lateral force trans- mission between adjacent fascicles is relatively smal , and therefore the fascicles might be considered to be func- tional y independent structures.26 The fact that sliding Fascicle, Ø 0.1–4 mm can occur between fascicles might be advantageous as, for example, tendons wrap around bones. The inter- fascicular space contains fibroblasts, capil aries, nerves and small- diameter fibrils, 26 and it remains unknown if the structures in this space would be adversely affected by disproportionately large shear or possible focal adhe- sions, or both. It is, however, important to underline that Fibril, Ø 30–300 nm mechanical stimulation of fibroblasts located between fascicles is important for the synthesis of collagen and the release of growth factors.
the extracel ular matrix are damaged owing to large shear tensile-bearing units of tendon. Lower right corner inset: TeM cross-sectional area showing the fibril diameter distribution (30–300 nm). The interfibril ar space is the forces between fibrils.
of the tropo collagen molecule might elongate, the gap α-chains to form a triple helix. Abbreviation: TeM, transmission electron micrograph.
strain regulates the col agen protein synthesis response. of knee extension (70% 1 repetition maximum). The graph It is hypothesized that insufficient recovery time will tilt indicates a similar increase in collagen synthesis the balance between col agen synthesis and degradation, independent of exercise volume (repetitions), which resulting in a net catabolic state.
suggests that there is a ceiling effect in collagen synthesis. It also indicates that adding exercise repetitions (cumulative load) wil not increase col agen synthesis further, but potential y increase degradation and further amplify a Habitual loading (as occurs in response to training) wil negative net balance in collagen.
result in a higher rate of collagen synthesis in the basal state simply as a result of the constant effect of loading in microdialysis fluid representing the tendon inter stitial from the previous 24–48 h; this effect can be seen at the concentration.80 A key regulator of col agen syn thesis is level of the whole tendon as tendon hypertrophy.68 The rate IGF-1, which has a stimulatory effect on col agen protein of degradation also increases with training to ensure that synthesis in vitro and in vivo.79,81 TGF-β and CTGF the overall turnover is high, but not to the same extent stimulate fibroblasts within the patella tendon to syn- as the increase in synthesis, which allows for a small—but thesize collagen,82 and exercise seems to enhance this consistent—positive net balance of col agen.69 Habitual effect.83 Interestingly, the expression of both IGF-1 and training thus results in a higher turnover of collagen, TGF-β mRnA rises in response to exercise independent whereas inactivity lowers col agen synthesis and turn- of muscular contraction type,78 which suggests that both over.70 This result il ustrates why activity even in the pres- growth factors are important regulators of col agen syn- ence of tendino pathy might be better for the regeneration thesis in tendon. surprisingly, inactivity by suspension of of the tendon tissue than complete inactivity.
the hindlimb in rats or by lower limb casting in humans The fact that col agen and matrix proteins are impor- also resulted in an initial increase in the levels of IGF-1 tant in the development of tendinopathy is supported mRnA,84 which indicates an unloading IGF-1 response,85 by the fact that polymorphisms in the genes that encode or a compensatory increase in the synthesis of growth col ag en and tenascin C are associated with a higher than factors to counteract the inactivity-induced drop in col a- normal risk of developing tendinopathy (Box 1).71,72 In gen synthesis. when activity is resumed after a period addition to col agen, other matrix proteins also respond of rest, the expression of col agen is again normalized.84 to loading. several proteoglycans, such as decorin, ver- These findings demonstrate that inactivity does not sican, aggrecan, lumican, fibromodulin, keratocan and follow a pattern opposite to that of the loading response, proteoglycan 4, increase their turnover in response to and that this pattern might reflect a protective mechanism loading to maintain homeostasis in the tendon,73–77 which towards the loss of tendon tissue during inactivity. In any further supports the use of loading activity in the treat- case, these responses do not favor inactivity as a treatment ment of tendinopathy. Final y, the expression of enzymes for tendinopathy.
ated with neovascularization and elevated intratendinous Genetic variations have been implicated in the development of tendinopathies. The blood flow99–101 that seems to normalize during the course collagen, type V, alpha 1 (COL5A1) and TNC genes encode the col agen alpha-1(V) of exercise-based conservative treatment.100 Increased flow chain and tenascin C, both of which are important structural components in tendons during exercise probably represents a physio logically and ligaments; variations within these genes, along with variations in the gene important response, whereas an elevated flow in the encoding matrix metalloproteinase 3, have been shown to cosegregate with chronic Achilles tendinopathy.71,72 The collagen alpha-1(V) chain is involved in the assembly resting state accompanies tendinopathy. However, rather of collagen fibers and influences fiber diameter, and variations in this component than being important in the pathogenesis of tendino pathy, might alter collagen strength. Similarly, tenascin C is known to be involved in the latter response represents a secondary regenerative the response of collagen to mechanical loading in a dose-dependent manner. The phenomenon. Indeed, the elevated flow during loading genes encoding these proteins have also been shown to be associated with anterior might be advantageous for tendinopathy. In patients with cruciate ligament ruptures.109,110 These data indicate that genetic variations might clinical signs of tendinopathy and hypervascularization, be involved in the development of certain tendon pathologies.
it has been suggested that the primary source of pain is the result of nerves growing intimately with the new Young women—especial y if taking estrogen-containing vessels into the tendons.102 It has been demonstrated that oral contraceptives—demonstrate lower basal levels of tendon tissue injury (partial rupture model) leads to both collagen and a lower increase in collagen synthesis in an angiogenic response103 and marked nerve ingrowth, response to loading compared with males.87–89 This result as well as the presence of substance P and calcitonin- might explain why women show an attenuated adaptive gene-related peptide, both of which are involved in pain tendon response with habitual loading,90 and why they transmission.104,105 These newly formed nerves and blood might need longer for tendon adaptation to loading. The vessels disappear during healing, a process that is accel- lower increase in col agen synthesis in response to loading erated with physical activity and delayed with prolonged might also explain why women are more susceptible to inactivity in the recovery phase.106,107 How nerve ingrowth certain soft tissue overload injuries.91 The mechanism occurs in tendinopathy is unclear, but the process seems to remains unknown, but as estrogen levels are inversely occur subsequently to alterations in protein synthesis, and related to the levels of IGF-1 in tissues, estrogen might might therefore explain why clinical pain occurs when the exert its inhibiting effect indirectly via attenuating the tendinopathy is already quite advanced.
tissue is part of the physiological response to load ing, Understanding how tendon tissue adapts to mechanical and blocking this response has been shown to inhibit the loading, and how and when this process is attenuated synthesis of collagen protein (s. G. Petersen, l. Holm, during tendinopathy, will contribute to our understand- M. Kjaer, unpublished work). such inhibition is in line ing of the pathogenesis of this condition. In part, the with what is known to occur in skeletal muscle contractile limited knowledge of the pathogenesis of tendinopathy protein92 and for skeletal muscle stem cel s (satellite cel s).93 resides in the fact that the actual injury mechanisms are levels of inflammatory mediators in tendino pathy are not quite advanced before symptoms are experienced by elevated in the resting state,94 which further supports the the patient. new methods, such as tissue biopsy sam- notion that tendinopathy is not an inflammatory condi- pling, infusion of growth factors and determining local tion. However, the inflam matory response might increase tissue reactions to acute loading or overloading by use of immediately after exercise, despite the absence of inflam- microdialysis, have yielded promising new information matory cel s in the chronical y overloaded tendons, indi- on the turnover of the connective tissue. An intervention cating a susceptibility of the overloaded tissue towards an model that combines immobilization with acute loading increase in inflammation with loading. This result would might also unveil the pathways of overloading in fragile explain the difference between the lack of inflammatory (immobilized) tissue. To study the actual injury mecha- observations during surgery and the documented positive nism and the early stages of the injury, it might be useful short-term effect of anti- inflammatory medication (for to turn to animal models, the use of which has already example, glucocortico id injection) in tendinopathy.
step in the development of more effective treatment and Poor blood supply has been implicated as a factor con- tributing to tendon injuries, but tendon vascularization appears ample both around and inside the tendon in patients with tendinopathy.95,96 During exercise, the blood flow of tendon can increase by up to seven-fold, and it is we searched for original articles focusing on tendinopathy mainly regulated by the release of prosta glandins. This in MeDLINe and PubMed, published between 1970 and response only represents 20% of the maximal capacity of 2009. The search terms we used were "tendinosis", the tendon during ischemic reperfusion,97 and therefore "tendinitis", "tendinopathy", "collagen" and "fibroblast". blood flow is remarkably low during rest. In individuals All papers identified were english-language, full text who undergo extensive physical training, resting blood papers. we also searched the reference lists of identified flow is not elevated.
0 Macmil an Publishers Limited. Al rights reserved 1. Finni, T., Komi, P. V. & Lepola, V. In vivo human 22. Barnard, K., Light, N. D., Sims, T. J. & Bailey, A. J. 41. Arnoczky, S. P., Lavagnino, M. & egerbacher, M. triceps surae and quadriceps femoris muscle Chemistry of the collagen cross-links. Origin and The mechanobiological aetiopathogenesis of function in a squat jump and counter movement partial characterization of a putative mature tendinopathy: is it the over-stimulation or the jump. Eur. J. Appl. Physiol. 83, 416–426 (2000).
cross-link of collagen. Biochem. J. 244, 303–309 under-stimulation of tendon cells? Int. J. Exp. 2. Giddings, V. L., Beaupre, G. S., whalen, R. T. & Pathol. 88, 217–226 (2007).
Carter, D. R. Calcaneal loading during walking 23. Riley, G. P. Gene expression and matrix turnover 42. Danielson, P., Andersson, G., Alfredson, H. & and running. Med. Sci. Sports Exerc. 32, in overused and damaged tendons. Scand. J. Forsgren, S. extensive expression of markers for 627–634 (2000).
Med. Sci. Sports 15, 241–251 (2005).
acetylcholine synthesis and of M2 receptors in 3. Magnusson, S. P., Aagaard, P., Dyhre-Poulsen, P. & 24. Kjaer, M. Role of extracellular matrix in adaptation tenocytes in therapy-resistant chronic painful Kjaer, M. Load-displacement properties of the of tendon and skeletal muscle to mechanical patellar tendon tendinosis—a pilot study. Life human triceps surae aponeurosis in vivo. loading. Physiol. Rev. 84, 649–698 (2004).
J. Physiol. 531, 277–288 (2001).
25. Haraldsson, B. T. et al. Region-specific 43. Riley, G. P., Goddard, M. J. & Hazleman, B. L. 4. Khan, K. & Cook, J. The painful nonruptured mechanical properties of the human patella Histopathological assessment and pathological tendon: clinical aspects. Clin. Sports Med. 22, tendon. J. Appl. Physiol. 98, 1006–1012 (2005).
significance of matrix degeneration in 711–725 (2003).
26. Haraldsson, B. T. et al. Lateral force supraspinatus tendons. Rheumatology (Oxford) 5. Maffulli, N., Khan, K. M. & Puddu, G. Overuse transmission between human tendon fascicles. 40, 229–230 (2001).
tendon conditions: time to change a confusing Matrix Biol. 27, 86–95 (2008).
44. Lian, O. et al. excessive apoptosis in patellar terminology. Arthroscopy 14, 840–843 (1998).
27. Parry, D. A., Barnes, G. R. & Craig, A. S. tendinopathy in athletes. Am. J. Sports Med. 35, 6. Ferretti, A. epidemiology of jumper's knee. A comparison of the size distribution of collagen 605–611 (2007).
Sports Med. 3, 289–295 (1986).
fibrils in connective tissues as a function of age 45. Scott, A. et al. High strain mechanical loading 7. Frost, P. et al. Risk of shoulder tendinitis in relation and a possible relation between fibril size rapidly induces tendon apoptosis: an ex vivo rat to shoulder loads in monotonous repetitive work. distribution and mechanical properties. Proc. R. tibialis anterior model. Br. J. Sports Med. 39, e25 Am. J. Ind. Med. 41, 11–18 (2002).
Soc. Lond. B Biol. Sci. 203, 305–321 (1978).
8. Tanaka, S., Petersen, M. & Cameron, L. 28. Lujan, T. J., Underwood, C. J., Jacobs, N. T. & 46. wang, F., Murrell, G. A. & wang, M. X. Oxidative Prevalence and risk factors of tendinitis and weiss, J. A. Contribution of glycosaminoglycans stress-induced c-Jun N.-terminal kinase (JNK) related disorders of the distal upper extremity to viscoelastic tensile behavior of human activation in tendon cells upregulates MMP1 among U. S. workers: comparison to carpal tunnel ligament. J. Appl. Physiol. 106, 423–431 (2009).
mRNA and protein expression. J. Orthop. Res. syndrome. Am. J. Ind. Med. 39, 328–335 (2001).
29. Provenzano, P. P. & Vanderby, R. Jr. Collagen fibril 25, 378–389 (2007).
9. Gruchow, H. w. & Pelletier, D. An epidemiologic morphology and organization: implications for 47. Yuan, J., Murrell, G. A., Trickett, A. & wang, M. X. study of tennis elbow. Incidence, recurrence, and force transmission in ligament and tendon. Involvement of cytochrome c release and effectiveness of prevention strategies. Am. J. Matrix Biol. 25, 71–84 (2006).
caspase-3 activation in the oxidative stress- Sports Med. 7, 234–238 (1979).
30. Scott, J. e. elasticity in extracellular matrix induced apoptosis in human tendon fibroblasts. 10. Lian, O. B., engebretsen, L. & Bahr, R. ‘shape modules' of tendon, cartilage, etc. A Biochim. Biophys. Acta 1641, 35–41 (2003).
Prevalence of jumper's knee among elite sliding proteoglycan-filament model. J. Physiol. 48. Corps, A. N. et al. The regulation of aggrecanase athletes from different sports: a cross-sectional 553, 335–343 (2003).
ADAMTS-4 expression in human Achilles tendon study. Am. J. Sports Med. 33, 561–567 (2005).
31. Puxkandl, R. et al. Viscoelastic properties of and tendon-derived cells. Matrix Biol. 27, 11. Knobloch, K., Yoon, U. & Vogt, P. M. Acute and collagen: synchrotron radiation investigations 393–401 (2008).
overuse injuries correlated to hours of training in and structural model. Philos. Trans. R. Soc. Lond. 49. Corps, A. N. et al. Versican splice variant master running athletes. Foot Ankle Int. 29, B Biol. Sci. 357, 191–197 (2002).
messenger RNA expression in normal human 671–676 (2008).
32. Mosler, e. et al. Stress-induced molecular Achilles tendon and tendinopathies. 12. Kettunen, J. A., Kvist, M., Alanen, e. & rearrangement in tendon collagen. J. Mol. Biol. Rheumatology (Oxford) 43, 969–972 (2004).
Kujala, U. M. Long-term prognosis for jumper's 182, 589–596 (1985).
50. Jones, G. C. et al. expression profiling of knee in male athletes. A prospective follow-up 33. Dahners, L. e., Lester, G. e. & Caprise, P. The metalloproteinases and tissue inhibitors study. Am. J. Sports Med. 30, 689–692 (2002).
pentapeptide NKISK affects collagen fibril of metalloproteinases in normal and degenerate 13. Bojsen-Moller, J., Kalliokoski, K. K., interactions in a vertebrate tissue. J. Orthop. human achilles tendon. Arthritis Rheum. 54, Seppanen, M., Kjaer, M. & Magnusson, S. P. Res. 18, 532–536 (2000).
Low-intensity tensile loading increases 34. Buehler, M. J. Nanomechanics of collagen fibrils 51. Corps, A. N. et al. Increased expression of intratendinous glucose uptake in the Achilles under varying cross-link densities: atomistic and aggrecan and biglycan mRNA in Achilles tendon. J. Appl. Physiol. 101, 196–201 (2006).
continuum studies. J. Mech. Behav. Biomed. tendinopathy. Rheumatology (Oxford) 45, 14. Langberg, H., Rosendal, L. & Kjaer, M. Training- Mater. 1, 59–67 (2008).
induced changes in peritendinous type I collagen 35. Fratzl, P. et al. Fibrillar structure and mechanical 52. Corps, A. N., Curry, V. A., Buttle, D. J., turnover determined by microdialysis in humans. properties of collagen. J. Struct. Biol. 122, Hazleman, B. L. & Riley, G. P. Inhibition of J. Physiol. 534, 297–302 (2001).
interleukin-1β-stimulated collagenase and 15. Ker, R. F., Alexander, R. M. & Bennett, M. B. why 36. Sasaki, N. & Odajima, S. elongation mechanism stromelysin expression in human tendon are mammalian tendons so thick? J. Zoo. Lond. of collagen fibrils and force-strain relations of fibroblasts by epigallocatechin gallate ester. 216, 309–324 (1988).
tendon at each level of structural hierarchy. Matrix Biol. 23, 163–169 (2004).
16. Komi, P. V., Fukashiro, S. & Jarvinen, M. J. Biomech. 29, 1131–1136 (1996).
53. Xu, Y. & Murrell, G. A. The basic science of Biomechanical loading of Achilles tendon during 37. Sasaki, N. & Odajima, S. Stress-strain curve and tendinopathy. Clin. Orthop. Relat. Res. 466, normal locomotion. Clin. Sports Med. 11, Young's modulus of a collagen molecule as 1528–1538 (2008).
determined by the X-ray diffraction technique. 54. Drummond, A. H. et al. Preclinical and clinical 17. Nakama, L. H., King, K. B., Abrahamsson, S. & J. Biomech. 29, 655–658 (1996).
studies of MMP inhibitors in cancer. Ann. NY Rempel, D. M. evidence of tendon microtears 38. Lorenzo, A. C. & Caffarena, e. R. elastic Acad. Sci. 878, 228–235 (1999).
due to cyclical loading in an in vivo tendinopathy properties, Young's modulus determination and 55. Jones, L., Ghaneh, P., Humphreys, M. & model. J. Orthop. Res. 23, 1199–1205 (2005).
structural stability of the tropocollagen Neoptolemos, J. P. The matrix 18. Ker, R. F. The implications of the adaptable molecule: a computational study by steered metalloproteinases and their inhibitors in the fatigue quality of tendons for their construction, molecular dynamics. J. Biomech. 38, treatment of pancreatic cancer. Ann. NY Acad. repair and function. Comp. Biochem. Physiol. A 1527–1533 (2005).
Mol. Integr. Physiol. 133, 987–1000 (2002).
39. Screen, H. R., Lee, D. A., Bader, D. L. & 56. Archambault, J. M. et al. Rat supraspinatus 19. Kastelic, J., Galeski, A. & Baer, e. The Shelton, J. C. An investigation into the effects of tendon expresses cartilage markers with multicomposite structure of tendon. Connect. the hierarchical structure of tendon fascicles on overuse. J. Orthop. Res. 25, 617–624 (2007).
Tissue Res. 6, 11–23 (1978).
micromechanical properties. Proc. Inst. Mech. 57. Goncalves-Neto, J. et al. Changes in collagen 20. Kadler, K. e., Holmes, D. F., Trotter, J. A. & Eng. H 218, 109–119 (2004).
matrix composition in human posterior tibial Chapman, J. A. Collagen fibril formation. 40. Arnoczky, S. P., Lavagnino, M., whallon, J. H. & tendon dysfunction. Joint Bone Spine 69, Biochem. J. 316 (Pt 1), 1–11 (1996).
Hoonjan, A. In situ cell nucleus deformation in 189–194 (2002).
21. Bailey, A. J. Molecular mechanisms of ageing in tendons under tensile load; a morphological 58. Riley, G. P. et al. Tendon degeneration and chronic connective tissues. Mech. Ageing Dev. 122, analysis using confocal laser microscopy. shoulder pain: changes in the collagen 735–755 (2001).
J. Orthop. Res. 20, 29–35 (2002).
0 Macmil an Publishers Limited. Al rights reserved in rotator cuff tendinitis. Ann. Rheum. Dis. 53, fibromodulin-deficient mice. J. Biol. Chem. 277, myogenic precursor cell responses in humans. 359–366 (1994).
J. Appl. Physiol. 103, 425–431 (2007).
59. Bank, R. A., TeKoppele, J. M., Oostingh, G., 76. Iozzo, R. V. The biology of the small leucine-rich 94. Alfredson, H., Thorsen, K. & Lorentzon, R. In situ Hazleman, B. L. & Riley, G. P. Lysylhydroxylation proteoglycans. Functional network of interactive microdialysis in tendon tissue: high levels of and non-reducible crosslinking of human proteins. J. Biol. Chem. 274, 18843–18846 glutamate, but not prostaglandin e2 in chronic supraspinatus tendon collagen: changes with Achilles tendon pain. Knee Surg. Sports age and in chronic rotator cuff tendinitis. Ann. 77. Rees, S. G., waggett, A. D., Dent, C. M. & Traumatol. Arthrosc. 7, 378–381 (1999).
Rheum. Dis. 58, 35–41 (1999).
Caterson, B. Inhibition of aggrecan turnover in 95. Schatzker, J. & Branemark, P. I. Intravital 60. de Mos, M. et al. Achilles tendinosis: changes in short-term explant cultures of bovine tendon. observations on the microvascular anatomy and biochemical composition and collagen turnover Matrix Biol. 26, 280–290 (2007).
microcirculation of the tendon. Acta Orthop. rate. Am. J. Sports Med. 35, 1549–1556 (2007).
78. Olesen, J. L. et al. expression, content, and Scand. Suppl. 126, 1–23 (1969).
61. Riley, G. P., Harrall, R. L., Cawston, T. e., localization of insulin-like growth factor I in 96. Astrom, M. & westlin, N. Blood flow in the human Hazleman, B. L. & Mackie, e. J. Tenascin-C and human achilles tendon. Connect. Tissue Res. 47, Achilles tendon assessed by laser Doppler human tendon degeneration. Am. J. Pathol. 149, 200–206 (2006).
flowmetry. J. Orthop. Res. 12, 246–252 (1994).
79. Kjaer, M. et al. From mechanical loading to 97. Boushel, R. et al. Blood flow and oxygenation in 62. Bi, Y. et al. Identification of tendon stem/ collagen synthesis, structural changes and peritendinous tissue and calf muscle during progenitor cells and the role of the extracellular function in human tendon. Scand. J. Med. Sci. dynamic exercise in humans. J. Physiol. 524 matrix in their niche. Nat. Med. 13, 1219–1227 Sports 19, 500–510 (2009).
80. Langberg, H., Olesen, J. L., Gemmer, C. & 98. de Vos, R. J., weir, A., Cobben, L. P. & Tol, J. L. 63. Lejard, V. et al. Scleraxis and NFATc regulate the Kjaer, M. Substantial elevation of interleukin-6 The value of power Doppler ultrasonography in expression of the pro-alpha1(I) collagen gene in concentration in peritendinous tissue, in Achilles tendinopathy: a prospective study. Am. J. tendon fibroblasts. J. Biol. Chem. 282, contrast to muscle, following prolonged exercise Sports Med. 35, 1696–1701 (2007).
in humans. J. Physiol. 542, 985–990 (2002).
99. Astrom, M. & westlin, N. Blood flow in chronic 64. Heinemeier, K. M. et al. expression of collagen 81. Abrahamsson, S. O. Similar effects of Achilles tendinopathy. Clin. Orthop. Relat. Res. and related growth factors in rat tendon and recombinant human insulin-like growth factor-I 308, 166–172 (1994).
skeletal muscle in response to specific and II on cellular activities in flexor tendons of 100. Ohberg, L. & Alfredson, H. effects on contraction types. J. Physiol. 582, 1303–1316 young rabbits: experimental studies in vitro. neovascularisation behind the good results with J. Orthop. Res. 15, 256–262 (1997).
eccentric training in chronic mid-portion Achilles 65. Miller, B. F. et al. Coordinated collagen and 82. Schild, C. & Trueb, B. Mechanical stress is tendinosis? Knee Surg. Sports Traumatol. muscle protein synthesis in human patella required for high-level expression of connective Arthrosc. 12, 465–470 (2004).
tendon and quadriceps muscle after exercise. tissue growth factor. Exp. Cell Res. 274, 83–91 101. Hoksrud, A., Ohberg, L., Alfredson, H. & Bahr, R. J. Physiol. 567, 1021–1033 (2005).
Color Doppler ultrasound findings in patellar 66. Langberg, H., Skovgaard, D., Karamouzis, M., 83. Yang, G., Crawford, R. C. & wang, J. H. tendinopathy (jumper's knee). Am. J. Sports Med. Bulow, J. & Kjaer, M. Metabolism and Proliferation and collagen production of human 36, 1813–1820 (2008).
inflammatory mediators in the peritendinous patellar tendon fibroblasts in response to cyclic 102. Ackermann, P. w., Salo, P. T. & Hart, D. A. space measured by microdialysis during uniaxial stretching in serum-free conditions. Neuronal pathways in tendon healing. Front. intermittent isometric exercise in humans. J. Biomech. 37, 1543–1550 (2004).
J. Physiol. 515, 919–927 (1999).
84. Heinemeier, K. M. et al. effect of unloading 103. Pufe, T., Petersen, w. J., Mentlein, R. & 67. Koskinen, S. O., Heinemeier, K. M., Olesen, J. L., followed by reloading on expression of collagen Tillmann, B. N. The role of vasculature and Langberg, H. & Kjaer, M. Physical exercise can and related growth factors in rat tendon and angiogenesis for the pathogenesis of influence local levels of matrix muscle. J. Appl. Physiol. 106, 178–186 (2009).
degenerative tendons disease. Scand. J. Med. metalloproteinases and their inhibitors in 85. Sakata, T. et al. Skeletal unloading induces Sci. Sports 15, 211–222 (2005).
tendon-related connective tissue. J. Appl. Physiol. resistance to insulin-like growth factor-I (IGF-I) by 104. Ackermann, P. w., Finn, A. & Ahmed, M. Sensory 96, 861–864 (2004).
inhibiting activation of the IGF-I signaling neuropeptidergic pattern in tendon, ligament 68. Couppe, C. et al. Habitual loading results in pathways. J. Bone Miner. Res. 19, 436–446 and joint capsule. A study in the rat. Neuroreport tendon hypertrophy and increased stiffness of 10, 2055–2060 (1999).
the human patellar tendon. J. Appl. Physiol. 105, 86. Yu, w. D., Panossian, V., Hatch, J. D., Liu, S. H. & 105. Ackermann, P. w., Li, J., Finn, A., Ahmed, M. & 805–810 (2008).
Finerman, G. A. Combined effects of estrogen Kreicbergs, A. Autonomic innervation of tendons, 69. Kovanen, V. effects of ageing and physical and progesterone on the anterior cruciate ligaments and joint capsules. A morphologic and training on rat skeletal muscle. An experimental ligament. Clin. Orthop. Relat. Res. 383, 268–281 quantitative study in the rat. J. Orthop. Res. 19, study on the properties of col agen, laminin, and 372–378 (2001).
fibre types in muscles serving different functions. 87. Miller, B. F. et al. Tendon collagen synthesis at 106. Bring, D. K., Kreicbergs, A., Renstrom, P. A. & Acta Physiol. Scand. Suppl. 577, 1–56 (1989).
rest and after exercise in women. J. Appl. Physiol. Ackermann, P. w. Physical activity modulates 70. de Boer, M. D. et al. The temporal responses of 102, 541–546 (2007).
nerve plasticity and stimulates repair after protein synthesis, gene expression and cell 88. Miller, B. F. et al. No effect of menstrual cycle on Achilles tendon rupture. J. Orthop. Res. 25, signalling in human quadriceps muscle and myofibrillar and connective tissue protein 164–172 (2007).
patellar tendon to disuse. J. Physiol. 585, synthesis in contracting skeletal muscle. Am. J. 107. Bring, D. K. et al. Joint immobilization reduces 241–251 (2007).
Physiol. Endocrinol. Metab. 290, e163–e168 the expression of sensory neuropeptide 71. Mokone, G. G. et al. The guanine-thymine receptors and impairs healing after tendon dinucleotide repeat polymorphism within the 89. Hansen, M. et al. effect of administration of oral rupture in a rat model. J. Orthop. Res. 27, tenascin-C gene is associated with achilles contraceptives in vivo on col agen synthesis in 274–280 (2009).
tendon injuries. Am. J. Sports Med. 33, tendon and muscle connective tissue in young 108. Glazebrook, M. A., wright, J. R., Jr, Langman, M., 1016–1021 (2005).
women. J. Appl. Physiol. 106, 1435–1443 (2009).
Stanish, w. D. & Lee, J. M. Histological analysis 72. Mokone, G. G., Schwellnus, M. P., Noakes, T. D. & 90. westh, e. et al. effect of habitual exercise on the of achilles tendons in an overuse rat model. Collins, M. The COL5A1 gene and Achilles structural and mechanical properties of human J. Orthop. Res. 26, 840–846 (2008).
tendon pathology. Scand. J. Med. Sci. Sports 16, tendon, in vivo, in men and women. Scand. J. 109. September, A. V., Schwellnus, M. P. & Collins, M. 19–26 (2006).
Med. Sci. Sports 18, 23–30 (2008).
Tendon and ligament injuries: the genetic 73. Rees, S. G., Dent, C. M. & Caterson, B. 91. Hewett, T. e., Myer, G. D. & Ford, K. R. Anterior component. Br. J. Sports Med. 41, 241–246 Metabolism of proteoglycans in tendon. Scand. J. cruciate ligament injuries in female athletes: Med. Sci. Sports 19, 470–478 (2009).
Part 1, mechanisms and risk factors. Am. J. 110. Collins, M. & Raleigh, S. M. Genetic risk factors 74. Samiric, T., Ilic, M. Z. & Handley, C. J. Large Sports Med. 34, 299–311 (2006).
for musculoskeletal soft tissue injuries. Med. aggregating and small leucine-rich proteoglycans 92. Trappe, T. A. et al. effect of ibuprofen and Sport Sci. 54, 136–149 (2009).
are degraded by different pathways and at acetaminophen on postexercise muscle protein 111. Langberg, H., Skovgaard, D., Petersen, L. J., different rates in tendon. Eur. J. Biochem. 271, synthesis. Am. J. Physiol. Endocrinol. Metab. 282, Bulow, J. & Kjaer, M. Type I col agen synthesis and 3612–3620 (2004).
degradation in peritendinous tissue after exercise 75. Jepsen, K. J. et al. A syndrome of joint laxity and 93. Mackey, A. L. et al. The influence of anti- determined by microdialysis in humans. J. Physiol. impaired tendon integrity in lumican- and inflammatory medication on exercise-induced 521 (Pt 1), 299–306 (1999).

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