Abstract
Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy.
Key Points
-
Tendon disorders are common, often under-reported and a major clinical problem
-
Most current treatments for tendinopathy are neither effective nor evidence-based
-
Molecular processes underlying tendinopathy are now being elucidated: metalloproteinase enzymes are thought to have a key role in the regulation of the activity of tendon cells and matrix remodeling in both normal and pathologic tendon
-
The potential roles of neuropeptides, inflammatory mediators and mechanical strain (either too much or too little) acting on the resident tenocytes are the source of some controversy and require in-depth investigation using in vitro and in vivo models
-
Excessive or inappropriate activity of destructive matrix-degrading enzymes might be a novel therapeutic target for tendinopathy; other treatments in development include the injection of stem cells, gene therapy and tissue engineering to repair or replace damaged tendon tissue
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Badley EM and Tennant A (1993) Impact of disablement due to rheumatic disorders in a British population: estimates of severity and prevalence from the Calderdale Rheumatic Disablement Survey. Ann Rheum Dis 52: 6–13
McCormick A et al. (1995) Assessing health needs in primary care. Morbidity study from general practice provides another source of information. BMJ 310: 1534
Chard MD et al. (1991) Shoulder disorders in the elderly: a community survey. Arthritis Rheum 34: 766–769
Bamji AN et al. (1990) What do rheumatologists do? A pilot audit study. Br J Rheumatol 29: 295–298
Puddu G et al. (1976) A classification of Achilles tendon disease. Am J Sports Med 4: 145–150
Almekinders LC and Temple JD (1998) Etiology, diagnosis, and treatment of tendonitis: an analysis of the literature. Med Sci Sports Exerc 30: 1183–1190
McLauchlan GJ and Handoll HHG. Interventions for treating acute and chronic Achilles tendinitis. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000232. 10.1002/14651858. CD000232
Riley GP (2004) Tendon and ligament biochemistry and pathology. In Soft Tissue Rheumatology, 20–53 (Eds Hazleman BL et al.) Oxford: Oxford University Press
Benjamin M (2004) The structure and function of tendons. In Soft Tissue Rheumatology, 9–19 (Eds Hazleman BL et al.) Oxford: Oxford University Press
Salingcarnboriboon R et al. (2003) Establishment of tendon-derived cell lines exhibiting pluripotent mesenchymal stem cell-like property. Exp Cell Res 287: 289–300
Józsa L and Kannus P (1997) Structure and metabolism of normal tendons. In Human Tendons. Anatomy, Physiology and Pathology (Eds Józsa L and Kannus P) Champaign, IL: Human Kinetics
Banes AJ et al. (1988) Cell populations of tendon: a simplified method for isolation of synovial cells and internal fibroblasts: confirmation of origin and biologic properties. J Orthop Res 6: 83–94
Ehlers TW and Vogel KG (1998) Proteoglycan synthesis by fibroblasts from different regions of bovine tendon cultured in alginate beads. Comp Biochem Physiol A Mol Integr Physiol 121: 355–363
Lavagnino M and Arnoczky SP (2005) In vitro alterations in cytoskeletal tensional homeostasis control gene expression in tendon cells. J Orthop Res 23: 1211–1218
Bjur D et al. (2005) 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 320: 201–206
Jones ME et al. (2003) The early surface cell response to flexor tendon injury. J Hand Surg (Am) 28: 221–230
Ker RF et al. (2000) Fatigue quality of mammalian tendons. J Exp Biol 203: 1317–1327
Bank RA et al. (1999) Lysylhydroxylation and non-reducible cross-linking of human supraspinatus tendon collagen: changes with age and in chronic rotator cuff tendinitis. Ann Rheum Dis 58: 35–41
Riley GP et al. (2002) Matrix metalloproteinase activities and their relationship with collagen remodelling in tendon pathology. Matrix Biol 21: 185–195
Rees SG et al. (2000) Catabolism of aggrecan, decorin and biglycan in tendon. Biochem J 350: 181–188
Samiric T et al. (2004) Characterisation of proteoglycans and their catabolic products in tendon and explant cultures of tendon. Matrix Biol 23: 127–140
Nagase H et al. (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69: 562–573
Jones GC and Riley GP (2005) ADAMTS proteinases: a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis. Arthritis Res Ther 7: 160–169
Jones GC et al. (2006) Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon. Arthritis Rheum 54: 832–842
McCawley LJ and Matrisian LM (2001) Matrix metalloproteinases: they're not just for matrix anymore! Curr Opin Cell Biol 13: 534–540
Drummond AH et al. (1999) Preclinical and clinical studies of MMP inhibitors in cancer. Ann N Y Acad Sci 878: 228–235
Corps AN et al. (2002) Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1 beta in human tendon-derived cells. A potential mechanism of fluoroquinolone-induced tendinopathy. Arthritis Rheum 46: 3034–3040
Pasternak B et al. (2006) Doxycycline impairs tendon repair in rats. Acta Orthop Belg 72: 756–760
Cook JL and Khan KM (2007) Etiology of tendinopathy. In Tendinopathy in Athletes, 10–28 (Eds Woo SL et al.) Oxford: Blackwell Publishing Ltd
Aström M and Rausing A (1995) Chronic Achilles tendinopathy. A survey of surgical and histopathologic findings. Clin Orthop Relat Res 316: 151–164
Ohberg L et al. (2001) Neovascularisation in Achilles tendons with painful tendinosis but not in normal tendons: an ultrasonographic investigation. Knee Surg Sports Traumatol Arthrosc 9: 233–238
Kannus P and Józsa L (1991) Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J Bone Joint Surg Am 73: 1507–1525
Riley G (2004) The pathogenesis of tendinopathy. A molecular perspective. Rheumatology (Oxford) 43: 131–142
Corps AN et al. (2006) Increased expression of aggrecan and biglycan mRNA in Achilles tendinopathy. Rheumatology (Oxford) 45: 291–294
Corps AN et al. (2004) Versican splice variant messenger RNA expression in normal human Achilles tendon and tendinopathies. Rheumatology (Oxford) 43: 969–972
Wewer UM et al. (2005) ADAM12: the long and short of it. In The ADAM Family of Proteases, 123–146 (Eds Hooper N and Lendeckel U) London: Kluwer Academic/Springer
Clancy BM et al. (2003) A gene expression profile for endochondral bone formation: oligonucleotide microarrays establish novel connections between known genes and BMP-2-induced bone formation in mouse quadriceps. Bone 33: 46–63
Archambault J et al. (2002) Stretch and interleukin-1beta induce matrix metalloproteinases in rabbit tendon cells in vitro. J Orthop Res 20: 36–39
Arnoczky SP et al. (2004) Ex vivo static tensile loading inhibits MMP-1 expression in rat tail tendon cells through a cytoskeletally based mechanotransduction mechanism. J Orthop Res 22: 328–333
Lavagnino M et al. (2005) Isolated fibrillar damage in tendons stimulates local collagenase mRNA expression and protein synthesis. J Biomech 39: 2355–2362
Alfredson H et al. (1999) 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
Alfredson H et al. (2001) 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 19: 881–886
Langberg H et al. (1999) Metabolism and inflammatory mediators in the peritendinous space measured by microdialysis during intermittent isometric exercise in humans. J Physiol 515: 919–927
Langberg H et al. (2002) Exercise-induced increase in interstitial bradykinin and adenosine concentrations in skeletal muscle and peritendinous tissue in humans. J Physiol 542: 977–983
Langberg H et al. (2002) Substantial elevation of interleukin-6 concentration in peritendinous tissue, in contrast to muscle, following prolonged exercise in humans. J Physiol 542: 985–990
Gotoh M et al. (2001) Interleukin-1-induced subacromial synovitis and shoulder pain in rotator cuff diseases. Rheumatology 40: 995–1001
Fu SC et al. (2002) Increased expression of transforming growth factor-beta1 in patellar tendinosis. Clin Orthop Relat Res 400: 174–183
Khan MH et al. (2005) Repeated exposure of tendon to prostaglandin-E2 leads to localized tendon degeneration. Clin J Sport Med 15: 27–33
Gotoh M et al. (1998) Increased substance P in subacromial bursa and shoulder pain in rotator cuff diseases. J Orthop Res 16: 618–621
Fenwick SA et al. (2001) Expression of transforming growth factor-beta isoforms and their receptors in chronic tendinosis. J Anat 199: 231–240
Alfredson H et al. (2002) High intratendinous lactate levels in painful chronic Achilles tendinosis. An investigation using microdialysis technique. J Orthop Res 20: 934–938
Murrell GAC et al. (1997) Modulation of tendon healing by nitric oxide. Inflamm Res 46: 19–27
Burssens P et al. (2005) Exogenously administered substance P and neutral endopeptidase inhibitors stimulate fibroblast proliferation, angiogenesis and collagen organization during Achilles tendon healing. Foot Ankle Int 26: 832–839
Alfredson H et al. (1998) Heavy-load eccentric calf muscle training for the treatment of chronic Achilles tendinosis. Am J Sports Med 26: 360–366
Mafi N et al. (2001) Superior short-term results with eccentric calf muscle training compared to concentric training in a randomized prospective multicenter study on patients with chronic Achilles tendinosis. Knee Surg Sports Traumatol Arthrosc 9: 42–47
Woodley BL et al. (2007) Chronic tendinopathy: effectiveness of eccentric exercise. Br J Sports Med 41: 188–198
Rompe JD et al. (2007) Eccentric loading, shock-wave treatment, or a wait-and-see policy for tendinopathy of the main body of tendo Achillis: a randomized controlled trial. Am J Sports Med 35: 374–383
Speed CA (2004) Extracorporeal shock-wave therapy in the management of chronic soft-tissue conditions. J Bone Joint Surg Br 86: 165–171
D'Vaz AP et al. (2006) Pulsed low-intensity ultrasound therapy for chronic lateral epicondylitis: a randomized controlled trial. Rheumatology (Oxford) 45: 566–570
Paoloni JA et al. (2003) Topical nitric oxide application in the treatment of chronic extensor tendinosis at the elbow: a randomized, double-blinded, placebo-controlled clinical trial. Am J Sports Med 31: 915–920
Paoloni JA et al. (2004) Topical glyceryl trinitrate treatment of chronic noninsertional achilles tendinopathy. A randomized, double-blind, placebo-controlled trial. J Bone Joint Surg Am 86-A: 916–922
Paoloni JA et al. (2005) Topical glyceryl trinitrate application in the treatment of chronic supraspinatus tendinopathy: a randomized, double-blinded, placebo-controlled clinical trial. Am J Sports Med 33: 806–813
Alfredson H and Ohberg L (2005) Sclerosing injections to areas of neo-vascularisation reduce pain in chronic Achilles tendinopathy: a double-blind randomised controlled trial. Knee Surg Sports Traumatol Arthrosc 13: 338–344
Pufe T et al. (2001) The angiogenic peptide vascular endothelial growth factor is expressed in foetal and ruptured tendons. Virchows Arch 439: 579–585
Pufe T et al. (2003) Mechanical factors influence the expression of endostatin—an inhibitor of angiogenesis—in tendons. J Orthop Res 21: 610–616
Smith RK (2006) Stem cell technology in equine tendon and ligament injuries. Vet Rec 158: 140
Gerich TG et al. (1996) Gene transfer to the rabbit patellar tendon: potential for genetic enhancement of tendon and ligament healing. Gene Ther 3: 1089–1093
Awad HA et al. (2000) In vitro characterization of mesenchymal stem cell-seeded collagen scaffolds for tendon repair: effects of initial seeding density on contraction kinetics. J Biomed Mater Res 51: 233–240
Carpenter JE et al. (1999) Animal models of tendon and ligament injuries for tissue engineering applications. Clin Orthop Rel Res 367 (Suppl): S296–S311
Archambault JM et al. (2007) Rat supraspinatus tendon expresses cartilage markers with overuse. J Orthop Res 25: 617–624
Acknowledgements
The author would like to acknowledge all members of the Rheumatology Research Unit, Addenbrooke's Hospital, Cambridge, past and present, who have contributed so much to his studies on tendon pathology over the years. He would also like to thank all his collaborators, in addition to the surgeons, physicians and scientists who have provided materials and technical and intellectual support. His work would also have been impossible without the financial support of many funding agencies: in particular, the Arthritis Research Campaign, Action Medical Research, Dunhill Medical Trust, REMEDI, Rosetrees Trust, Elkin Charitable Foundation and the Isaac Newton Trust. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscapeaccredited continuing medical education activity associated with this article.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
G Riley has acted as a Consultant for Wyeth Pharmaceuticals.
Rights and permissions
About this article
Cite this article
Riley, G. Tendinopathy—from basic science to treatment. Nat Rev Rheumatol 4, 82–89 (2008). https://doi.org/10.1038/ncprheum0700
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncprheum0700
This article is cited by
-
Longitudinal Evidence for High-Level Patellar Tendon Strain as a Risk Factor for Tendinopathy in Adolescent Athletes
Sports Medicine - Open (2023)
-
Three-Dimensional Cell Culture System for Tendon Tissue Engineering
Tissue Engineering and Regenerative Medicine (2023)
-
Challenges and perspectives of tendon-derived cell therapy for tendinopathy: from bench to bedside
Stem Cell Research & Therapy (2022)
-
A criteria-based rehabilitation program for chronic mid-portion Achilles tendinopathy: study protocol for a randomised controlled trial
BMC Musculoskeletal Disorders (2021)
-
TGF-β3 regulates adhesion formation through the JNK/c-Jun pathway during flexor tendon healing
BMC Musculoskeletal Disorders (2021)