Throw away the anti-inflammatories & start loading your damaged tendons
Evidence into practice
– Written by Michael Kjaer, Denmark
Tendons in our body ensure that muscle contractile force is transferred to bone and thereby enables locomotor function. When we exercise, we are exposed to high amounts of loading which tissue adapts to, some more so than others. Whereas the skeletal and heart musculature can adapt quite dramatically with training, the adaptive response of connective tissue, such as tendon, which is dominated by collagen, is more moderate. From human studies we know that collagen synthesis rises in response to loading1, and that although this indicates that one of the building blocks for the tendon is formed, it does not guarantee any new tendon structure formation. Accordingly, it has been revealed that the core of the human Achilles tendon has almost no turnover in adult life2, which fits with observations of horse tendons3. Despite this lack of evidence for any structural changes in the tendon with regular physical activity after the age of 18, tendon hypertrophy is seen in response to long-term training with exercises that load the Achilles tendon4. So, what could potentially happen with training is the addition of thin layers of collagen tissue on the surface of the tendon, almost like adding ‘rings’ to a tree as it grows older, or it may be that the tendon has a small modifiable turnover pool of collagen that in itself has no influence on the primary structure of the tendon. With loading of the tendon, the blood flow, metabolism and the peritendinous concentration of inflammatory markers like prostaglandins can be upregulated5,6. Along with these responses, collagen proteolytic enzyme activity and collagen degradation are also found to increase7.
During exercise, blood flow of the tendon can increase up to 10-fold in an intensity-dependent manner8, and when prostaglandin release is inhibited by anti-inflammatory medication, this exercise-induced rise in tendon blood flow can be reduced by approximately 30%. This effect is specific for cyclooxygenase-2 (Cox-2) mediated pathways, in accordance with this pathway being inducible by exercise. This indicates that an increase in tissue prostaglandin plays a significant role for blood flow in tendon connective tissue during physical loading in vivo. In support of a connection between tendon loading and release of inflammatory mediators, tendons from mice subjected to treadmill running showed increased concentrations of prostaglandins. In vitro studies on human fibroblasts also show a rise in production of inflammatory mediators in a stretching magnitude-dependent pattern9.
TENDON TISSUE FORMATION AND INFLAMMATION
It has been shown that anti-inflammatory medication was able to diminish the prostaglandin response to mechanical loading of human fibroblasts isolated either from the patellar tendon or the hand tendon stretched in vitro10,11. The effect of anti-inflammatory medication on the local prostaglandin level in the human patellar tendon was also lower for 3 days after exercise compared to the non-blocked tendon12. Also, the exercise-induced increase in tendon collagen synthesis was reduced. These findings suggest that intact activation of inflammatory pathways is important for the physiological rise in the collagen synthesis that is seen with mechanical loading of tendon tissue. The influence of anti-inflammatory medication on the training-related adaptation of human tendons has been investigated in both young and elderly individuals. No significant adaptation in the morphological tendon size was seen, whereas the normalised tendon deformation and strain decreased with training, but medication did not change this outcome of training13. This suggests that tendon tissue shows no substantial change in tendon content of collagen or fibrillar structures but may modify its mechanical properties through, for example, cross links, and that such changes are not diminished with the administration of anti-inflammatory medication. Interleukins have been suggested to play a role in tendon adaptation to loading. Prolonged running results in a rise in the tissue concentration of interleukin-6 (IL-6). Based on this, the exercise-induced rise in interleukins was suggested to be the ‘inflammation-mediator’ of mechanical stimulation of collagen synthesis. When human recombinant IL-6 was infused locally, collagen synthesis in the peritendinous tissue rose to a similar degree as with exercise14. This suggests that IL-6 is an important stimulator of collagen synthesis, and can act independently of any mechanical tendon loading.
INFLAMMATION, EXERCISE AND PROTEOLYSIS
Proteolytic activity of the tendon can increase in response to acute exercise. Further, in vitro studies on rabbit tendon showed that the combination of mechanical stretch and the inflammatory cytokine IL-1b synergistically increased the expression and activity of proteolytic enzymes15. Also, human patellar tendon fibroblasts responded to IL-1b with increased proteolytic expression9. This suggests that mechanical loading, together with inflammatory cytokines, can alter matrix proteolytic enzymatic activity. IL-1b and mechanical stretch can both induce COX-2 expression in tendon fibroblasts as individual treatments, and combining these two treatments can induce a more pronounced response. However, low doses of IL-1b can also repress expression of some genes induced by mechanical stretch16. Thus, it appears that there are some interactions between inflammatory cytokines, loading and the potential for matrix degradation. Interestingly, studies have shown that mechanical loading was necessary to protect tendon collagen bundles cultured in the presence of inflammatory cells from degradation and loss of mechanical integrity17,18. This suggests that mechanical loading is a primary mechanism for reducing susceptibility of collagen fibrils in tendon tissue to enzymatic degradation. This protective effect of tensile strain is supported by findings made in other collagen-rich connective tissues, and underlines the importance of mechanical tension for tendon homeostasis. It appears that inflammatory mediators do play a role in the adaptation of healthy human tendon tissue to mechanical loading. Thus, both inflammatory markers and collagen turnover are modulated in the peritendinous tissue with loading, and the removal of the inflammatory response to physiological tissue loading seems detrimental for the collagen response.
TENDINOPATHY AND INFLAMMATION
Tendinopathy displays characteristics of degenerative changes in the tissue but in general lacks signs of inflammatory responses19. Tendinopathic tendon demo-nstrates changes in cell shape and density, presented as a rounding of the normally elongated tendon fibroblasts and showing areas of increased cell density as well as areas with very low cell numbers. In addition, the normally well-aligned collagen fibres lose their organisation and a thickening of the tendon due to accumulation of proteoglycans, and thus water is seen19. In addition, a chronic up-regulation of the expression of several structural proteins, proteolytic enzymes and growth factors is observed in tendinopathy19. However, there is no sign of any up-regulation in the expression of inflammatory signal mediators. Somewhat in contradiction to the lack of inflammatory up-regulation in tendinopathic tendon is the demonstration – in the short-term, at least – of a clinical effect of anti-inflammatory treatment with glucocorticoids20. This could be because when at rest, no inflammatory signs are present, whereas during times like after heavy mechanical loading (e.g. running) an inflammatory response could potentially be present. However, in patients with chronic tendinopathy, a presence of inflammatory mediators in response to acute running was not shown, and subsequently nor was any influence of inflammatory medication21. This finding demonstrates that inflam-matory signalling is not exaggerated in tendinopathic compared to healthy regions of the tendon after physical activity. In line with this, no convincing evidence exists for the substantial historical use of anti-inflammatory drugs in treatment of painful or overloaded tendons22. However, it cannot be excluded that tendinopathic conditions only demonstrate inflammatory characteristics very early in the disease. Several authors have suggested a two-phase response with an early inflammatory-dominated response followed by a later degenerative response23, whereas others maintain the idea that tendinopathy is a degenerative phenomenon with-out inflammation24. Presently, the full explanation for development of tendinopathy remains elusive with two suggestions being currently proposed. One theory posits that tendinopathy reflects a misbalance between overloading of the tissue resulting in both a cell reaction towards apoptosis and increased proteolytic activity25. An alternate theory suggests a local unloading of tendon cells due to micro-ruptures of collagen fibres as an initial step in pathological changes seen in tendon injuries26. In this scenario, it would be the absence of tensile stimuli that would trigger catabolic alterations of tendon tissue26.
TENDON RUPTURE AND INFLAMMATION
Rupture to the tendon and the subsequent healing is associated with inflammatory activity, and the initial inflammatory period is followed by a later period of proliferation and remodelling where inflammation is less pronounced and scar formation and fibrosis occur27. This supports the view that tendon healing has transient changes in the degree of inflammation present. The inflammatory phase seems to be influenced by the degree of mechanical loading during the healing process. When rat tendon was mechanically injured, inflammation-associated genes were altered both in response to a single loading episode or with more continuous loading28. The induced expression of inflammatory mediators during early tendon healing was lowered when tendons were loaded, and was coupled with an improved matrix synthesis and thicker, stronger tendons. This suggests a beneficial role of mechanical loading and inflammatory signalling upon tendon adaptation. Further, inhibition of inflammatory mediators during tendon healing after acute injury appears to inhibit the healing progression29.
In conclusion, studies on healthy tendons have shown that inflammatory markers and collagen turnover increase with loading. Inflammatory cytokines can mediate increased collagen synthesis in tendon connective tissue and inflammatory pathways regulate the exercise-mediated blood flow. Thus, anti-inflammatory treatment may inhibit physiological changes occurring in response to exercise. Chronic tendinopathy does not display any inflammation activity either at rest or after acute exercise, and thus the role of anti-inflammatory treatment may be minimal. In tendon rupture an early inflammatory response is seen, and studies on animals indicate that mechanical loading applied during regeneration of the tendon may modulate this response in a beneficial manner, whereas the guidelines for use of anti-inflammatory medication in relation to tendon rupture in humans are lacking evidence.
Michael Kjaer M.D. Ph.D.
Professor of Sports Medicine
Bispebjerg Hospital and Centre of Healthy Aging
University of Copenhagen
1. Miller BF, Olesen JL, Hansen M, Dossing S, Crameri RM, Welling RJ et al. Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise. J Physiol 2005; 567:1021-1033.
2.Heinemeier KM, Schjerling P, Heinemeier J, Magnusson SP, Kjaer M. Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb 14C. FASEB J 2013; 27:2074-2079.
3.Thorpe CT, Streeter I, Pinchbeck GL, Goodship AE, Clegg PD, Birch HL. Aspartic acid racemization and collagen degradation markers reveal an accumulation of damage in tendon collagen that is enhanced with aging. J Biol Chem 2010; 285:15674-15681.
4.Couppe C, Kongsgaard M, Aagaard P, Hansen P, Bojsen-Moller J, Kjaer M et al. Habitual loading results in tendon hypertrophy and increased stiffness of the human patellar tendon. J Appl Physiol 2008; 105:805-810.
5.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 1999; 515:919-927.
6.Langberg H, Olesen JL, Gemmer C, Kjaer M. Substantial elevation of interleukin-6 concentration in peritendinous tissue, in contrast to muscle, following prolonged exercise in humans. J Physiol 2002; 542:985-990.
7.Langberg H, Rosendal L, Kjær M. Training induced changes in peritendinous type I collagen turnover determined by microdialysis in humans. J.Physiol 2001; 534:297-302.
8.Langberg H, Boushel R, Skovgaard D, Risum N, Kjar M. Cyclo-oxygenase-2 mediated prostaglandin release regulates blood flow in connective tissue during mechanical loading in humans. J Physiol 2003; 551:683-689.
9.Yang G, Im HJ, Wang JH. Repetitive mechanical stretching modulates IL-1beta induced COX-2, MMP-1 expression, and PGE2 production in human patellar tendon fibroblasts. Gene 2005; 363:166-172.
10.Almekinders LC, Baynes AJ, Bracey LW. An in vitro investigation into the effects of repetitive motion and nonsteroidal antiinflammatory medication on human tendon fibroblasts. AmJ Sports Med 1995; 23:119-123.
11.Li Z, Yang G, Khan M, Stone D, Woo SL, Wang JH. Inflammatory response of human tendon fibroblasts to cyclic mechanical stretching. Am J Sports Med 2004; 32:435-440.
12.Christensen B, Dandanell S, Kjaer M, Langberg H. Effect of anti-inflammatory medication on the running-induced rise in patella tendon collagen synthesis in humans. J Appl Physiol 2011; 110:137-141.
13.Carroll CC, Dickinson JM, LeMoine JK, Haus JM, Weinheimer EM, Hollon CJ et al. Influence of acetaminophen and ibuprofen on in vivo patellar tendon adaptations to knee extensor resistance exercise in older adults. J Appl Physiol 2011; 111:508-515.
14.Andersen MB, Pingel J, Kjaer M, Langberg H. Interleukin-6: a growth factor stimulating collagen synthesis in human tendon. J Appl Physiol 2011; 110:1549-1554.
15.Archambault J, Tsuzaki M, Herzog W, Banes AJ. Stretch and interleukin-1beta induce matrix metalloproteinases in rabbit tendon cells in vitro. J Orthop Res 2002; 20:36-39.
16.Qi J, Chi L, Bynum D, Banes AJ. Gap junctions in IL-1beta-mediated cell survival response to strain. J Appl Physiol 2011; 110:1425-1431.
17.Marsolais D, Duchesne E, Cote CH, Frenette J. Inflammatory cells do not decrease the ultimate tensile strength of intact tendons in vivo and in vitro: protective role of mechanical loading. J Appl Physiol 2007; 102:11-17.
18.Ruberti JW, Hallab NJ. Strain-controlled enzymatic cleavage of collagen in loaded matrix. Biochem Biophys Res Commun 2005; 336:483-489.
19.Riley G. Tendinopathy--from basic science to treatment. Nat Clin Pract Rheumatol 2008; 4:82-89.
20.Coombes BK, Bisset L, Vicenzino B. Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials. Lancet 2010; 376:1751-1767.
21.Pingel J, Fredberg U, Qvortrup K, Larsen JO, Schjerling P, Heinemeier KM et al. Local biochemical and morphological changes in human Achilles tendinopathy: A case control study. BMC Musculoskelet Disord 2012; 13:53.
22.Andres BM, Murrell GA. Treatment of tendinopathy: what works, what does not, and what is on the horizon. Clinical Orthop Relat Res 2008; 466:1539-1554.
23.Millar NL, Murrell GA. Heat shock proteins in tendinopathy: novel molecular regulators. Mediators Inflamm 2012; 2012:436203.
24.Thornton GM, Hart DA. The interface of mechanical loading and biological variables as they pertain to the development of tendinosis. J Musculoskelet Neuronal Interact 2011; 11:94-105.
25.Magnusson SP, Langberg H, Kjaer M. The pathogenesis of tendinopathy: balancing the response to loading. Nat Rev Rheumatol 2010; 6:262-268.
26.Arnoczky SP, 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 2007; 88:217-226.
27.Schulze-Tanzil G, Al-Sadi O, Wiegand E, Ertel W, Busch C, Kohl B et al. The role of pro-inflammatory and immunoregulatory cytokines in tendon healing and rupture: new insights. Scand J Med Sci Sports 2011; 21:337-351.
28.Eliasson P, Andersson T, Aspenberg P. Influence of a single loading episode on gene expression in healing rat Achilles tendons. J Appl Physiol 2012; 112:279-288.
29.Murrell GA, Szabo C, Hannafin JA, Jang D, Dolan MM, Deng XH et al. Modulation of tendon healing by nitric oxide. Inflamm Res 1997; 46:19-27.
30.Kjaer M. Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. Physiol Rev 2004; 84:649-698.
Image via David K