Biochemical Causes of Patellar Tendinopathy?

  • Patrik Danielson
  • Alexander Scott


During recent years, increasing attention has been devoted to the biochemical milieu of human tendons. Prompted by the lack of evident causality in the aetiology of tendinopathy, much contemporary research is focused on the possible roles of biochemical agents in the development of tendon symptoms and tissue changes. Although further experiments testing the functional importance of such biochemical mediators in tendinopathy are greatly needed, evidence of a dramatic metamorphosis in local cell signalling within chronically painful tendons exists. The evidence for biochemical aspects of tendinopathy that has consequently emerged might complement, rather than replace, existing theories on pathogenesis (see Chap. 15). It furthermore fits a theoretical model in which tendon pathology exists on a continuum which, at various points, involves abnormalities in blood vessels, nerves, tenocytes, and extracellular matrix.14 The aim of this chapter is to present the evidence that supports this biochemical model of patellar tendinopathy.


Patellar Tendon Tendon Tissue Patellar Tendinopathy Tendon Pathology Nerve Terminals21 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1.  1.
    Alfredson H. The chronic painful Achilles and patellar tendon: research on basic biology and treatment. Scand J Med Sci Sports. 2005;15:252-259.PubMedCrossRefGoogle Scholar
  2.  2.
    Alfredson H, Forsgren S, Thorsen K, et al. In vivo microdialysis and immunohistochemical analyses of tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of inflammation, in Jumper’s knee. J Orthop Res. 2001;19:881-886.PubMedCrossRefGoogle Scholar
  3.  3.
    Alfredson H, Ohberg L. Neovascularisation in chronic painful patellar tendinosis – promising results after sclerosing neovessels outside the tendon challenge the need for ­surgery. Knee Surg Sports Traumatol Arthrosc. 2005;13:74-80.PubMedCrossRefGoogle Scholar
  4.  4.
    Andersson G, Danielson P, Alfredson H, et al. Presence of substance P and the neurokinin-1 receptor in tenocytes of the human Achilles tendon. Regul Pept. 2008;150:81-87.PubMedCrossRefGoogle Scholar
  5.  5.
    Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain. 2000;16:S12-S20.PubMedCrossRefGoogle Scholar
  6.  6.
    Baron R, Levine JD, Fields HL. Causalgia and reflex sym­pathetic dystrophy: does the sympathetic nervous system contribute to the generation of pain? Muscle Nerve. 1999;22:678-695.PubMedCrossRefGoogle Scholar
  7.  7.
    Bjur D, Alfredson H, Forsgren S. The innervation pattern of the human Achilles tendon: studies of the normal and tendinosis tendon with markers for general and sensory innervation. Cell Tissue Res. 2005;320:201-206.PubMedCrossRefGoogle Scholar
  8.  8.
    Bjur DK, Alfredson HK, Forsgren SK. Presence of the neuropeptide Y 1 receptor in tenocytes and blood vessel walls in the human Achilles tendon. Br J Sports Med. 2009;43(14): 1136-1142.PubMedCrossRefGoogle Scholar
  9.  9.
    Bjur D, Danielson P, Alfredson H, et al. Immunohistochemical and in situ hybridization observations favor a local catecholamine production in the human Achilles tendon. Histol Histopathol. 2008;23:197-208.PubMedGoogle Scholar
  10. 10.
    Bjur D, Danielson P, Alfredson H, et al. Presence of a non-neuronal cholinergic system and occurrence of up- and down-regulation in expression of M2 muscarinic acetylcholine receptors: new aspects of importance regarding Achilles tendon tendinosis (tendinopathy). Cell Tissue Res. 2008;331: 385-400.PubMedCrossRefGoogle Scholar
  11. 11.
    Burniston JG, Tan LB, Goldspink DF. Beta2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle. J Appl Physiol. 2005;98:1379-1386.PubMedCrossRefGoogle Scholar
  12. 12.
    Cook JL, Malliaras P, De Luca J, et al. Neovascularization and pain in abnormal patellar tendons of active jumping athletes. Clin J Sport Med. 2004;14:296-299.PubMedCrossRefGoogle Scholar
  13. 13.
    Cook JL, Malliaras P, De Luca J, et al. Vascularity and pain in the patellar tendon of adult jumping athletes: a 5 month longitudinal study. Br J Sports Med. 2005;39:458-461.PubMedCrossRefGoogle Scholar
  14. 14.
    Cook JL, Purdam CR. Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy. Br J Sports Med. 2009;43:409-416.PubMedCrossRefGoogle Scholar
  15. 15.
    Danielson P, Alfredson H, Forsgren S. Distribution of general (PGP 9.5) and sensory (substance P/CGRP) innervations in the human patellar tendon. Knee Surg Sports Traumatol Arthrosc. 2006;14:125-132.PubMedCrossRefGoogle Scholar
  16. 16.
    Danielson P, Alfredson H, Forsgren S. Immunohistochemical and histochemical findings favoring the occurrence of autocrine/paracrine as well as nerve-related cholinergic effects in chronic painful patellar tendon tendinosis. Microsc Res Tech. 2006;69:808-819.PubMedCrossRefGoogle Scholar
  17. 17.
    Danielson P, Alfredson H, Forsgren S. In situ hybridization studies confirming recent findings of the existence of a local nonneuronal catecholamine production in human patellar tendinosis. Microsc Res Tech. 2007;70:908-911.PubMedCrossRefGoogle Scholar
  18. 18.
    Danielson P, Alfredson H, Forsgren S. Studies on the importance of sympathetic innervation, adrenergic receptors, and a possible local catecholamine production in the development of patellar tendinopathy (tendinosis) in man. Microsc Res Tech. 2007;70:310-324.PubMedCrossRefGoogle Scholar
  19. 19.
    Danielson P, Andersson G, Alfredson H, et al. 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. 2007;80:2235-2238.PubMedCrossRefGoogle Scholar
  20. 20.
    Dussor GO, Helesic G, Hargreaves KM, et al. Cholinergic modulation of nociceptive responses in vivo and neuropeptide release in vitro at the level of the primary sensory neuron. Pain. 2004;107:22-32.PubMedCrossRefGoogle Scholar
  21. 21.
    Eiden LE. The cholinergic gene locus. J Neurochem. 1998;70:2227-2240.PubMedCrossRefGoogle Scholar
  22. 22.
    Forsgren S, Danielson P, Alfredson H. Vascular NK-1 receptor occurrence in normal and chronic painful Achilles and patellar tendons: studies on chemically unfixed as well as fixed specimens. Regul Pept. 2005;126:173-181.PubMedCrossRefGoogle Scholar
  23. 23.
    Gazerani P, Wang K, Cairns BE, et al. Effects of subcutaneous administration of glutamate on pain, sensitization and vasomotor responses in healthy men and women. Pain. 2006;124:338-348.PubMedCrossRefGoogle Scholar
  24. 24.
    Gisslen K, Alfredson H. Neovascularisation and pain in jumper’s knee: a prospective clinical and sonographic study in elite junior volleyball players. Br J Sports Med. 2005;39: 423-428.PubMedCrossRefGoogle Scholar
  25. 25.
    Haberberger RV, Bodenbenner M. Immunohistochemical localization of muscarinic receptors (M2) in the rat skin. Cell Tissue Res. 2000;300:389-396.PubMedCrossRefGoogle Scholar
  26. 26.
    Jacobi J, Jang JJ, Sundram U, et al. Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice. Am J Pathol. 2002;161:97-104.PubMedCrossRefGoogle Scholar
  27. 27.
    Kalariti N, Pissimissis N, Koutsilieris M. The glutamatergic system outside the CNS and in cancer biology. Expert Opin Investig Drugs. 2005;14:1487-1496.PubMedCrossRefGoogle Scholar
  28. 28.
    Kawashima K, Fujii T. The lymphocytic cholinergic system and its contribution to the regulation of immune activity. Life Sci. 2003;74:675-696.PubMedCrossRefGoogle Scholar
  29. 29.
    Khan KM, Bonar F, Desmond PM, et al. Patellar tendinosis (jumper’s knee): findings at histopathologic examination, US, and MR imaging. Victorian Institute of Sport Tendon Study Group. Radiology. 1996;200:821-827.PubMedGoogle Scholar
  30. 30.
    Khan KM, Cook JL, Bonar F, et al. Histopathology of common tendinopathies. Update and implications for clinical management. Sports Med. 1999;27:393-408.PubMedCrossRefGoogle Scholar
  31. 31.
    Khan KM, Cook JL, Maffulli N, et al. Where is the pain coming from in tendinopathy? It may be biochemical, not only structural, in origin. Br J Sports Med. 2000;34:81-83.PubMedCrossRefGoogle Scholar
  32. 32.
    Lian O, Dahl J, Ackermann PW, et al. Pronociceptive and antinociceptive neuromediators in patellar tendinopathy. Am J Sports Med. 2006;34:1801-1808.PubMedCrossRefGoogle Scholar
  33. 33.
    McMahon SB. Mechanisms of sympathetic pain. Br Med Bull. 1991;47:584-600.PubMedGoogle Scholar
  34. 34.
    Molloy TJ, Kemp MW, Wang Y, et al. Microarray analysis of the tendinopathic rat supraspinatus tendon: glutamate signaling and its potential role in tendon degeneration. J Appl Physiol. 2006;101:1702-1709.PubMedCrossRefGoogle Scholar
  35. 35.
    Oben JA, Diehl AM. Sympathetic nervous system regulation of liver repair. Anat Rec A Discov Mol Cell Evol Biol. 2004; 280:874-883.PubMedCrossRefGoogle Scholar
  36. 36.
    Oben JA, Roskams T, Yang S, et al. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut. 2004;53:438-445.PubMedCrossRefGoogle Scholar
  37. 37.
    Oben JA, Yang S, Lin H, et al. Acetylcholine promotes the proliferation and collagen gene expression of myofibroblastic hepatic stellate cells. Biochem Biophys Res Commun. 2003;300:172-177.PubMedCrossRefGoogle Scholar
  38. 38.
    Oben JA, Yang S, Lin H, et al. Norepinephrine and neuropeptide Y promote proliferation and collagen gene expression of hepatic myofibroblastic stellate cells. Biochem Biophys Res Commun. 2003;302:685-690.PubMedCrossRefGoogle Scholar
  39. 39.
    Schubert TE, Weidler C, Lerch K, et al. Achilles tendinosis is associated with sprouting of substance P positive nerve fibres. Ann Rheum Dis. 2005;64:1083-1086.PubMedCrossRefGoogle Scholar
  40. 40.
    Scott A, Alfredson H, Forsgren S. VGluT2 expression in painful Achilles and patellar tendinosis: evidence of local glutamate release by tenocytes. J Orthop Res. 2008;26:685-692.PubMedCrossRefGoogle Scholar
  41. 41.
    Scott A, Khan KM, Duronio V. IGF-I activates PKB and prevents anoxic apoptosis in Achilles tendon cells. J Orthop Res. 2005;23:1219-1225.PubMedCrossRefGoogle Scholar
  42. 42.
    Scott A, Khan KM, Heer J, et al. High strain mechanical loading rapidly induces tendon apoptosis: an ex vivo rat tibialis anterior model. Br J Sports Med. 2005;39:e25.PubMedCrossRefGoogle Scholar
  43. 43.
    Sekhon HS, Keller JA, Proskocil BJ, et al. Maternal nicotine exposure upregulates collagen gene expression in fetal monkey lung. Association with alpha7 nicotinic acetylcholine receptors. Am J Respir Cell Mol Biol. 2002;26:31-41.PubMedGoogle Scholar
  44. 44.
    Steen KH, Reeh PW. Actions of cholinergic agonists and antagonists on sensory nerve endings in rat skin, in vitro. J Neurophysiol. 1993;70:397-405.PubMedGoogle Scholar
  45. 45.
    Vogelsang M, Heyer G, Hornstein OP. Acetylcholine induces different cutaneous sensations in atopic and non-atopic subjects. Acta Derm Venereol. 1995;75:434-436.PubMedGoogle Scholar
  46. 46.
    Wessler I, Kilbinger H, Bittinger F, et al. The biological role of non-neuronal acetylcholine in plants and humans. Jpn J Pharmacol. 2001;85:2-10.PubMedCrossRefGoogle Scholar
  47. 47.
    Wessler I, Kirkpatrick CJ, Racke K. Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in humans. Pharmacol Ther. 1998;77:59-79.PubMedCrossRefGoogle Scholar
  48. 48.
    Wong HY. Neural mechanisms of joint pain. Ann Acad Med Singapore. 1993;22:646-650.PubMedGoogle Scholar
  49. 49.
    Yuan J, Wang MX, Murrell GA. Cell death and tendinopathy. Clin Sports Med. 2003;22:693-701.PubMedCrossRefGoogle Scholar
  50. 50.
    Zhang H, Faber JE. Trophic effect of norepinephrine on arterial intima-media and adventitia is augmented by injury and mediated by different alpha1-adrenoceptor subtypes. Circ Res. 2001;89:815-822.PubMedCrossRefGoogle Scholar

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© Springer-Verlag London Limited 2011

Authors and Affiliations

  1. 1.Department of Integrative Medical Biology, Section for Anatomy, Faculty of MedicineUmeå UniversityUmeåSweden

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