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The pathogenesis of tendinopathy: balancing the response to loading

Magnusson, S.P., Langberg, H. and Kjaer, M., 2010. The pathogenesis of tendinopathy: balancing the response to loading. Nature Reviews Rheumatology, 6(5), pp.262-268.

In today’s letter

• Overview of the paper discussing tendon response to loading

• Rapid Results = Tendons go through collagen creation & break down through a 72hours cycle and thus sensible loading needs to be implemented to avoid mal-adaption

• 3 Reads to check out to further you knowledge about tendon rehab

• Meme of the week: Hows the gait looking ? 👀

Aim of study

In this review, the authors explore the existing understanding of how different elements of the human tendon react to both short term and long term loading

Did you Know?

• Tendons are crucial for transmitting contractile forces to bone for movement and is uniquely designed to withstand significant loads (up to approximately 8 times body weight)

• Repetitive loading often results in overuse injuries, such as tendinopathy, a common clinical condition characterised by:

1. Pain during activity

2. Localised tenderness upon palpation

3. Swelling of the tendon

4. Impaired performance

• Tendinopathy affects both elite and recreational athletes, as well as workers.

• In some elite athletes, the prevalence can be as high as 45%, and the symptoms, along with any performance decrease, can be long-lasting (often many years).

• The injury mechanism is currently poorly understood. Human tendons, traditionally considered largely inert structures, are now known to be metabolically active in their response to mechanical loading.

Force and the tendon

• The average tensile stress on a tendon, which relates to the force transmitted and the area over which it is transmitted, depends on its cross-sectional area.

• Human tendons, such as the commonly affected patellar and Achilles tendons, typically have a fracture stress of approximately 100 MPa.

• Most tendons, however, are only subjected to stresses of up to 30 MPa, providing a reasonable safety margin, though the Achilles tendon may experience stresses up to around 70 MPa.

Structure of tendon tissue

• Tendons are organised in a highly structured, layered pattern. With collagen molecules being precisely arranged

• The collagen molecule is approximately 300 nm in length and 1.5 nm in diameter, and the aggregated molecules of the fibril are stabilised by covalent intermolecular crosslinks.

• These crosslinks bind the collagen molecules together, providing integrity to the fibril.

• Groups of fibrils form fibers known as fascicle bundles, which collectively make up the tendon

• Tendon tissue is predominantly composed of type I collagen.

Force transmission within the tendon

• The tendon can be functionally regarded as a single force-transmitting structure, but it is unknown if force are transmitted evenly throughout the tendon

• This raises a question about whether stress-strain on tendons is equal throughout the whole tendon

• It’s still unclear if there is a 'weak link' in force transmission and how tendons adapts to loading

• Fascicles from the front and back portions of the patellar tendon show significantly different mechanical properties.

• Lateral force transmission between fascicles is relatively small, indicating that fascicles might function as independent structures.

• Mechanical stimulation of fibroblasts located between fascicles is crucial for collagen synthesis and the release of growth factors.

• The collagen fibril is considered the fundamental force-transmitting unit of the tendon, but the actual length of fibrils is not fully understood, which hinders the detailed understanding of tendon force transmission.

• During tensile loading, fibroblasts and their cell nuclei, located between fibrils and in the interfascicular space, undergo deformation, which may be important in the mechanical signal transfer

• Loading can place strain on various components of the tendon, potentially contributing to 'injury' or material fatigue that requires repair.

• The repair process involves a balance between the synthesis and degradation of the various components of the extracellular matrix .

• It is important to note that too little stimulation (relative inactivity) might also disrupt this anabolic-catabolic balance.

Histological changes

• Typical pathological changes in tendinopathy include a reduction in the number of fibroblasts, fibroblast rounding, increased levels of proteoglycans, glycosaminoglycans, and water, hyper-vascularisation (with nerve ingrowth), and disorganised collagen fibrils.

• Tendinopathy tissue also shows an increased number of apoptotic cells, likely due to the activation of c-Jun N-terminal kinase and caspase-3 pathways as a result of mechanical loading.

Molecular changes

Changes in mRNA levels

• The molecular 'blueprint' of tendinopathy differs significantly from that of tendon rupture, suggesting different pathogenic mechanisms.

• Levels of mRNA encoding MMP3, MMP10, MMP12, and tissue inhibitor of metallo-proteinase (TIMP)-3 are lower in tendinopathy tissue compared to normal tissue, while mRNA expression levels of certain proteoglycans (such as decorin and versican) remain relatively unchanged.

• MMPs are crucial for the normal turnover of tendon proteins during homeostasis and repair, but these enzymes and their inhibitors may also play a role in tendon injury pathology.

Changes in protein levels

• In tendinopathy tissue, protein levels of type I collagen decrease while levels of type III collagen increase.

• Despite the correlation between collagen type III expression and protein content, the up-regulation of collagen type I expression does not lead to an increase in collagen I content.

• The mechanism behind this discrepancy is unknown, however, it is thought to disturb the normal homeostasis of collagen I in tendinopathic tendons.

• In tendinopathy, the amount of enzymatic crosslinking in collagen increases, while the amount of nonenzymatic crosslinking stays the same or decreases.

Enzymatic crosslinking refers to the process where enzymes create chemical bonds between collagen fibers, strengthening the overall structure of the tissue. This helps to stabilise and reinforce the tissue, making it more resistant to stress and damage

Strain and collagen synthesis

• Mechanical loading of tendons triggers an acute rise in collagen expression and increased protein synthesis in both animals and humans.

• This heightened collagen expression is likely controlled by strain on fibroblasts, stimulating a 2–3-fold increase in collagen formation peaking approximately 24 hours post-exercise, sustaining elevated levels for 70–80 hours.

• Collagen protein degradation also escalates in response to exercise, particularly early on and to a greater extent than synthesis.

• Following exercise cessation, a negative net balance in collagen levels persists for 18–36 hours (this timeframe can be shortened with improved training status), whereas a positive (anabolic) balance can endure for up to 72 hours post-exercise.

• These findings suggest that achieving a net increase in collagen requires adequate recovery ; insufficient rest may lead to ongoing collagen loss, potentially increasing tendon vulnerability to injury.

• Tendinopathy may therefore arise from an imbalance between protein synthesis and breakdown, particularly collagen.

• Interestingly, tendon loading increases collagen synthesis up to a point, but beyond that, more workload does not boost collagen production, meaning that fibroblasts have a maximum capacity for it.

Training/repetitive strain

• Regular loading due to training increases collagen synthesis rates due to the persistent loading effects from the previous 24–48 hours, resulting in tendon hypertrophy

• Training also increases the rate of collagen degradation to maintain high turnover, though not to the same extent as synthesis, ensuring a small but consistent positive net balance of collagen.

• Repeated training leads to elevated collagen turnover, whereas inactivity reduces both collagen synthesis and turnover.

• Apart from collagen, other matrix proteins also respond to loading; in response they increase their turnover, helping in tendon homeostasis.

• Enzymes involved in protein crosslinking expression are also up-regulated during exercise

Top 3 resources

To further your knowledge about tendon rehab

1. Maximising tendon adaptation - LINK

2. Returning to running after injury - LINK

3. The GOAT, Jill Cook talking about about tendon pathology and rehab (VIDEO) - LINK

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