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 upregulated^5,6. 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 vitro^10,11. 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 integrity^17,18. 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.

CONCLUSION

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

Copenhagen, Denmark

Contact: michaelkjaer@sund.ku.dk

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Image via David K