CORR Insights®: How Does Tendon Region, Donor, and the Presence of Disease Affect Protein Composition of the Achilles Tendon?

Where Are We Now?

The Achilles tendon is the strongest tendon in the body, but it is a source of restrictive activity-related pain and rupture during exertional activity. Problems related to this tendon have interested physicians since Hippocrates described the “tendo magnus” around 400 BC, which much later was named in honor of the Greek hero, Achilles. Despite this attention, and much extensive research since, the relative importance of the numerous factors that may contribute to Achilles tendinopathy and rupture is not agreed upon. Some of the factors that likely are important include age, sex, genetics, associated disease, vascularity, preexisting degeneration, muscle activation and fatigue, and treatment options. Nonetheless, we don’t know why a painless Achilles tendon should fail with one particular loaded step no different from thousands like it that a particular athlete may have taken before. Getting that answer, and sorting through the complex matrix of these factors that may be relevant, would help us better guide the patients we care for.

Achilles tendon disorders are responsible for considerable impairment of performance and function in athletes at all levels and in the population at large. Tendon rupture leads to a period of prolonged time away from work or sport [5], but even the most fundamental questions—like whether or not to operate, the timing of early or delayed rehabilitation, loading and motion, and when it’s safe to return to sport—remain controversial, and surgeons cannot guarantee a patient’s predictable return to performance and function at the end, whatever treatment is selected. Perhaps a more fundamental approach is called for; might we be able to determine what has led to a patient’s symptoms and possible failure by examining the protein makeup of an individual tendon?

In this month’s issue of Clinical Orthopaedics and Related Research®, Vaidya et al. [9] have taken cross-sectional specimens from the Achilles tendons of patients with Type 2 diabetes requiring amputation, “normal” tendons from patients requiring amputation for other reasons, and specimens from patients with Achilles tendinopathy who were treated surgically and looked in detail at the comparative protein composition of each group to try to identify mechanisms underlying tendon degeneration and function. Despite detailed assessment of these tendon samples, there was little difference between the diabetes and control populations, with reduced Type I collagen being the primary difference. In the tendinopathy group, differences in the extracellular matrix and inflammatory changes were the dominant finding, which suggests a role for dysregulated remodeling. This study [9] reinforces the belief that histopathology alone does not explain Achilles tendon tendinopathy but rather that degeneration and tendon failure are a function of a cascade of factors that affect tendon composition and symptoms, and that these factors are extrinsic as well as intrinsic.

Where Do We Need To Go?

Vaidya and colleagues [9] point to a number of factors that need to be considered outside the defined structural abnormalities in Achilles tendon injury and tendinopathy. Injury and tendinopathy have very different clinical pictures, and the paper shows clear differences in tendinopathy, particularly in the extracellular matrix, but minimal changes in two groups of patients (diabetes, nondiabetes) where you would think there would be clear structural differences at a cellular level. Even though preexisting, previously asymptomatic degeneration may occur in tendons that rupture, this doesn’t completely explain the catastrophic failure of such a robust tendon with minimal preexisting symptoms. Achilles tendon rupture then differs distinctly from the pain, discomfort, and exacerbation of symptoms at rest that characterize Achilles tendinopathy; this study in CORR® [9] identifies some disorganization of tendon structure with obvious abnormalities in the extracellular matrix as much as the structural tendon material, which may point a way toward refinement of our treatment approaches. To successfully treat tendinopathy, the ability to influence the extracellular matrix response to symptoms generated by structural abnormalities may help us help patients achieve symptomatic improvement and return of strength and function to the tendon [1]. Polidocanol sclerosing injections and platelet-rich plasma are part of a long list of proposed treatments that have shown early promise but unreliable long-term benefit. The strongest evidence is probably in favor of eccentric musculotendinous stretching and training in combination with appropriately delivered extracorporeal shockwave treatment, which has proven long-term benefit and low risk of tendon rupture [6]. However, I have concerns about this treatment. First, most studies on it find it superior to placebo, but not all of those studies have demonstrated that the effect size of that benefit is clinically important. And second, most studies on this topic have only short-term follow-up, causing me to wonder whether the symptoms might return.

Future studies also should better characterize what we think we know about afferent pain responses and identifying and influencing the nociceptors that are important for experiencing tendon pain, as occurs with the vascular proliferation associated with tendon inflammation. Removing pain as a restricting factor to gaining strength is a key goal of treatment in tendinopathy [1].

For tendon rupture, the way forward is even more uncertain. Are we able to identify those patients who are “at risk” of Achilles rupture and provide methods of specifically improving their tendon quality and reducing their risk? The fundamental question of how a tendon as strong as the Achilles that has been functioning with minimal symptoms can suddenly tear is still unclear. Is the causative factor for tendon rupture in such a tendon the progressive recruitment of muscle fibers in a fatiguing musculotendinous unit, followed by a reflex firing of all muscle units at maximum capacity when asked to provide a sudden, peak reflex response?

There are definite differences between individuals in their response to both surgical and nonsurgical treatment for Achilles tendon rupture, and some of these differences can be predicted at a genetic or cellular level. Identifying patients who are at greater risk of rerupture or poor outcome can influence rehabilitation, and possible adjuvants and supplements that may improve tendon healing seem to be a clear path forward for research and individualizing patient care pathways [4].

Genetic mapping for identifying individuals at greater risk of tendon injury or ligament rupture, as in the case of the Achilles tendon or the ACL, provides tantalizing potential for gene manipulation, as well as the philosophical arguments that go along with it [4, 7].

How Do We Get There?

In Achilles tendon rupture, it seems fundamental to understand why this tendon ruptures with one specific event that has usually been repeated many times before. Eight to twelve times body weight is required to rupture this tendon, and we still don’t understand why this happens at the specific time of injury. We know that as speed, force, and fatigue increase in sprinting or jumping, muscle fiber recruitment increases, but Achilles rupture is rarely seen in sprinters or high jumpers where it seems logical that maximal loads are applied. There appears to be a role for fatigue as part of the intensity of a muscle response. Analysis of data from GPS tracking and accelerometers in real-time monitoring of athlete movements, which is becoming more widely utilized, could allow detection of patterns of fatigue or movement changes that precede Achilles tendon rupture that support this concept. Similar theory has been utilized in Australian rules football prediction of hamstring injury [3].

With Achilles tendinopathy, effective manipulation of the extracellular matrix and reduction in the reactive changes that occur outside the collagen makeup of the tendon seems to be the area that is likely to yield the greatest benefit to our patients. Ultrasound assessment of the reduction in size of an affected tendon, either over time or compared with the nonsymptomatic side, provides an excellent tool for changes predominantly in the extracellular matrix, and using this to assess the immediate, medium-term, and long-term benefits of various local and systemic treatment options may allow us to quantify the value of the various combinations of the treatment modalities available.

Genetic typing of patients for both their risk of injury and the risk of a poorer outcome may help us to have much better markers of who is more likely to be injured and who is more likely to struggle with rehabilitation. How this information is utilized and who it is used to benefit the most—the healthcare provider, the employer, or the patient—is the concern in identifying this type of information. Genetic therapy and manipulation and regulation of gene-related cellular responses is a fascinating potential treatment modality in all branches of medicine and tendon injury, and tendinopathy is an area where this could play a role in the future.

In terms of aftercare following surgery and nonsurgical treatment of patients with tendinopathy, I believe that multimodal approaches likely are the way to go. Future studies should compare combinations of walking-assisted massage braces, provide more detailed study of how to successfully progress eccentric stretching and strengthening, and attempt to determine whether differences exist among different types of delivery systems for extracorporeal shockwave therapy.

Read This Next

• This article provides an excellent review of the current knowledge of the pathophysiology of Achilles tendinopathy [1].

• This study provides some insight into the concept of a mechanostat set point that can control the release of mRNA that may either have an anabolic or catabolic effect on the tendon cell and its surrounding extracellular matrix [2].

• This video captures the moment an elite athlete ruptures his Achilles tendon [8]. Why did it happen with this step at this particular time?