Achilles tendonitis and ruptures are a common injury especially among professional athletes and weekend warriors who participate in sports requiring bursts of jumping, pivoting and running.
A lot of big names in sports have been sidelined by Achilles tendon injury like the Los Angeles Rams cornerback Kayvon Webster, Memphis Grizzlies star point guard Mike Conley and the Baltimore Raven’s cornerback Jimmy Smith, and this is just in the last few weeks.
Recovery is a slow process and often complicated by chronic inflammation, a role in the progression of Achilles tendinopathy and rupture that is still little understood. Tendon disease has historically been described as ‘degenerative’, and therefore very little research has been devoted to investigating the role chronic inflammation may play in its progression.
That is until now.
A recent study, “Chronic inflammation is a feature of Achilles tendinopathy and rupture,” published online on November 8, 2017 in the British Journal of Sports Medicine, has taken a more in-depth look at what is happening on the cellular and molecular level in diseased Achilles tendons.
And the researchers have discovered that chronic inflammation does often occur with an Achilles tendon injury, and when not addressed properly it can complicate recovery.
To investigate the cellular and molecular features of inflammation in Achilles tendon disease, Stephanie Georgina Dakin, Ph.D., BVetMed, MRCVS, associate professor and director of the Taught MSc in Musculoskeletal Sciences at the University of Oxford in Oxford, England, and colleagues studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture and compared them to biopsies of patients with healthy hamstring tendons.
In total, 17 patients (7 female and 10 male) with Achilles tendinopathy, aged 41 to 74 years of age, 19 patients (4 female and 15 male) who had experienced an Achilles rupture were included in the study as well as 15 healthy patients who contributed healthy hamstring tendon samples for the study.
The Achilles tendinopathy samples were collected from patients who had presented for high-volume injection while the Achilles rupture samples came from patients who presented to a trauma unit for surgical debridement. The healthy hamstring tendon samples were donated by patients undergoing anterior cruciate ligament (ACL) reconstruction surgery.
Regarding methodology, the researchers acknowledged that there are potential limitations to using hamstring tendon as the point of comparison in the study because of difference in tendon type and possible differences in donor age, however they wrote that “this is preferable to using cadaveric Achilles tendon tissues, where the tissues can be affected by postmortem change and little is known about the health status of the tissue.”
“In addition, as sex distribution was not evenly matched between Achilles tissue cohorts, it was necessary to pool data for men and women.”
Markers of Chronic Inflammation
By looking for inflammation markers at the cellular and molecular level, Dakin and colleagues were able to see how the body responds to an Achilles tendon injury.
Using immunohistochemistry, they found that the cells in tendinopathic and ruptured Achilles expressed CD14+ and CD68+ cells at higher levels than healthy hamstring cells (p = 0.0015 and p = 0.0007, respectively).
The diseased cells also showed a complex inflammation signature, involving NF-κB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were also present in the tendinopathic samples while increased PTGS2 and interleukin-8 expression were observed in the Achilles ruptures.
Inflammatory pathways were also studied in cultured stromal fibroblasts from both healthy hamstring and diseased Achilles tendons, and all diseased samples were found to express podoplanin and CD106.
Dakins told OTW, “We used an established in vitro model to investigate how tendon stromal fibroblasts are implicated in sustaining inflammation.”
“Cells were isolated from biopsy samples of tendons from patients with Achilles tendinopathy and rupture. We stimulated these cells with cytokines known to induce expression of pro-inflammatory genes that we previously identified in diseased tendons.”
“This approach allows us to determine if cells from patients with Achilles tendinopathy or rupture are ‘primed’ to respond to a pro-inflammatory stimulus compared to cells from healthy volunteer tendons. Understanding how inflammation becomes chronic and fails to resolve is an important part of our research programme to identify effective new therapies to treat Achilles tendinopathy and rupture.”
Overall, the researchers found, there was an increased presence of pro-inflammatory and stromal fibroblast activation markers in the diseased tendon cells after cytokine stimulation as compared with the healthy hamstring cells. In addition, these diseased tendon tissues and cells besides showing evidence of chronic inflammation also share cellular and molecular inflammatory mechanisms with rotator cuff position tendons.
Dakins said, “Collectively our study showed that whilst energy storing Achilles tendons are functionally distinct to positional shoulder rotator cuff tendons, they share common cellular and molecular inflammatory mechanisms. These findings help inform the development of new therapeutic approaches that address the underlying biology of tendon disorders.”
New Therapies Needed
Dakins and colleagues suggested that the “differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo-vascularization.”
Unfortunately, some therapies used to treat Achilles tendon injuries can be problematic.
Medications and injections prescribed for pain and swelling can cause adverse effects and don’t address the central issue of chronic inflammation and the eccentric strengthening protocol often prescribed as a part of physical therapy while helpful if not done correctly can cause damage to the tendon.
In their study, the researchers recommend the use of treatment strategies that target non-resolving inflammation for patients with Achilles tendon disease and called for new therapeutic approaches that promote resolution of inflammation in chronic tendinopathy to be researched thoroughly.
Dakins told OTW, “Corticosteroids and NSAIDs [non-steroidal anti-inflammatory drugs] are frequently used in the medical management of Achilles tendon disorders.”
“However, corticosteroids can be associated with adverse effects such as tendon rupture, and prolonged use of NSAIDs to dampen inflammation can impair the body’s protective mechanisms that resolve inflammation.”
“We know that inflammation simply doesn’t fizzle out, it is regulated by an active ‘resolution’ process, the purpose of which is to restore the inflamed tissue to its previous healthy state.”
“We recently showed stromal fibroblasts from patients with chronic tendon inflammation show dysregulated resolution responses. Treatments that resolve inflammation are not yet clinically available, hence physical therapy and clinical monitoring are the main current treatments used for patients with Achilles tendinopathy and rupture.’
She said, “The findings from our study demonstrate that inflammation is an important feature of disease in patients with chronic Achilles tendinopathy or rupture.”
“In the early stage of tendon healing, inflammation has a protective role facilitating local tissue debridement, triggering tissue protective resolution responses and repair processes. However persistent non-resolving inflammation is damaging, resulting in chronic inflammation and fibrosis.”
“This knowledge helps to inform our therapeutic approach for patients with Achilles tendon disorders. Prolonged use of NSAIDs and long-acting corticosteroids further impair the body’s ability to resolve inflammation, so caution is advocated with long term use of these therapies for tendon disorders.”
