Why Failed Healing?

Why does the tendon fail to heal in tendinopathy? Researchers are trying to understand what goes wrong and how to fix it.

The Tendinopathy Cycle

The tendinopathy cycle begins when breakdown exceeds repair. Repetitive motion causes microinjuries that accumulate with time. Collagen breaks down and the tendon tries to repair itself, but the cells produce new collagen with an abnormal structure and composition.

The new collagen has an abnormally high Type III/Type I ratio. Experiments show that the excess Type III collagen at the expense of Type I collagen weakens the tendon, making it prone to further injury. Also, the new collagen fibers are less organized into the normal parallel structure, making the tendon less able to withstand tensile stress along the direction of the tendon.

Therefore, tendinopathy is a slow accumulation of little injuries that are not repaired properly and leave the tendon vulnerable to yet more injury. This failed healing process is the reason many people with tendinopathy don't completely heal from it and can't go back to their previous level of activity. Once the tendinopathy cycle starts, the tendon rarely heals back to its pre-injury state.

Although rest is an essential part of the healing process for tendinopathy, too much rest causes deconditioning of muscles and tendons.  The weaker muscles and tendons leave the area more vulnerable to injury. Thus, the area becomes weaker on a large scale as well as on a cellular scale. This cycle of injury/rest/deconditioning/more injury can be difficult to break.  Gradual, careful physical therapy exercises can help.

The tendinopathy cycle starts with overuse that leads to breakdown exceeding repair, which leads to abnormal collagen and weaker tendon, which leads to further injury and the cycle continues.

Abnormal Chromatin In Fibrocytes

Scar Tissue Formation

Researchers have long noticed that scar tissue can be a problem in the healing of chronic tendon injuries, and a 2019 study provides one explanation for this observation. A study published in Nature Cell Biology reported the first discovery of tendon stem cells and found that both the stem cells and fibrotic cells responded to platelet-derived growth factor alpha. If the tendon stem cells lose their ability to respond as well to the platelet-derived growth factor alpha, then the fibrotic cells will produce more scar tissue and the tendon stem cells won’t produce as much new tendon for repair. If researchers could find a way to help the tendon cells respond more and the scar tissue cells respond less, the balance might be tipped to better tendon healing with less scar tissue.

Poor Tendon Healing Capability and Changed Type I to III Collagen Ratio

Tendons and ligaments don't heal well to begin with, even when the injury does not become chronic. The strength of tendons and ligaments remains as much as 30% lower than normal even months or years following an acute injury.[7,8] Repair of acute injuries usually begins with the deposition of more Type III collagen than Type I, and the site gradually returns to a more normal composition and structure with time. The site can have an abnormally high Type III/Type I collagen ratio even after a year, and this abnormal collagen composition contributes to the weakness of the tissue.[7,8]  Possibly, some people with chronic injuries just never get past the initial phases of healing.

A team at the University of Glasgow is researching a possible way to correct the imbalance in Types I and III collagen in tendinopathy. They discovered that a microRNA called miR-29a can up-regulate the production of type I collagen relative to type III to restore collagen to pre-injury levels. Trials have been done in cultured cells and in mice, and horses will be next. One of their papers can be found here.

An abnormally high Type III/Type I ratio is a normal feature of the initial stages of tendon healing, but this ratio persists in tendinopathy. If some people start out with higher than normal Type III/Type I ratios in their tendons because of a genetic difference, it would make them more prone to tendinopathy because their tendons would be weaker. Once the tendinopathy cycle starts, these people would develop even higher Type III/Type I ratios in the injured areas, making it hard to break the cycle.

Changed Response to Growth Factors

Another possible explanation suggested for the abnormal collagen associated with chronic overuse injuries is that the fibroblasts could be damaged by long-term exposure to growth factors or by some other mechanism that makes them respond differently to growth factors. The repetitive motion causes tissue breakdown, which stimulates growth factors to make repairs; if more injury is done before the repairs are complete, the tissue is continually exposed to growth factors for long periods of time. The repetitive motion itself could even stimulate production of growth factors. Some researchers suggest that this long exposure to growth factors could make the cells produce abnormal collagen and that this cell behavior can become permanent even after the exposure to growth factors stops.[1]

In a previously mentioned study of carpal tunnel syndrome, cells were cultured from the wrist ligaments of injured patients and uninjured control patients.[1]  The cells were exposed to four different growth factors, including transforming growth factor beta (TGF-beta). The cells from injured patients produced abnormally high amounts of Type III collagen and low amounts of Type I collagen when exposed to the growth factors, as compared to cells from the control patients.

The authors conclude that the cells in the injured patients had been altered by the injury so that the response to growth factors was different. They hypothesize that one explanation for this change in response to growth factors is the long exposure to growth factors while the injury was accumulating. Their study demonstrates that using growth factors to try to treat chronic overuse injuries is a tricky proposition because the growth factors could have different effects on the injured cells than you might expect based on their effects on healthy cells.

Abnormal Levels of Proteolytic Enzymes

Proteolytic enzymes are substances that help break down proteins; they are used to break down old tissue in order to repair it and also to break down new proteins in the various stages of building new collagen fibers. For example, enzymes are needed to remove the extra sequences at the ends of procollagen to make tropocollagen that can then assemble into Type I, II, and III collagen fibers.

MMP-3, or stromelysin, is a proteolytic enzyme that is important in tissue remodeling. A study of Achilles tendinopathy found that tendons with tendinopathy had lower levels of MMP-3 mRNA than other tendons without tendinopathy in the same patients.[16] Even more interesting, the normal tendons of patients with tendinopathy had lower MMP-3 mRNA than tendons of control patients who had no tendinopathy anywhere. This study implies that differences exist not only between tendons with and without tendinopathy, but also between people who are and are not prone to tendinopathy. Maybe people who are prone start out with a lower rate of collagen turnover even before the injury cycle begins, possibly because of a down-regulation of proteolytic enzymes. This MMP-3 observation was made only in one small study, so more research is needed.

Of course too high a level of proteolytic enzymes can also be a problem. Normally, the body maintains a balance between proteolytic enzymes and their inhibitors to achieve a balance between tissue breakdown and repair.

Genetic Variants In Collagen

Some people seem to have genetic differences that make their tendons and ligaments weaker and more prone to tendinopathy. Multiple genetic variants likely exist that cause tendons and ligaments to be more prone to overuse injuries.

Many genetic defects in collagen have already been discovered. Some genetic defects cause fairly rare collagen disorders, such as Ehlers-Danlos Syndrome, but some cause more common problems like osteoporosis, osteoarthritis, and vertebral disk herniations. A colIA1 defect has been discovered to cause some cases of osteoporosis; the colIA1 defect causes weaker Type I collagen in the bones because of an abnormally high alpha1(I) to alpha2(I) ratio.[10,12]  A defect in Type II collagen has been associated with osteoarthritis. A colIXA2 defect is associated with an increased susceptibility to vertebral disk herniations (Type IX collagen is found in small amounts in vertebral disks).

The following list summarizes just a few of the genetic collagen abnormalities that seem to be associated with chronic tendon injuries.

  • Possible Genetic Abnormally High Type III/Type I Ratio: A high Type III/Type I collagen ratio has been associated with many overuse injuries. [1,6,9,13,14] The injury itself results in higher Type III/Type I, but perhaps some people have a genetic reason for a higher Type III to Type I collagen ratio in their tendons and ligaments to start with, and this would make them more prone to chronic overuse injuries. Some studies have shown that people with chronic TMJ problems have higher than normal Type III/Type I collagen ratios in their skin, and these people are also more prone to tendon overuse problems in many areas of their bodies. [6,14] Males seem less prone to chronic overuse injuries than females, and a few studies have found that males have higher total amounts of collagen in their tendons and lower Type III/Type I ratios.[5,6,11]

  • The COL5A1 Gene And Achilles Tendinopathy: A study found that the alpha 1 type V collagen gene COL5A1 BstUI RFLP has an association with chronic Achilles tendinopathy. Individuals with an A2 allele of this gene had lower risk of developing Achilles tendinopathy
  • MMP3 and COL5A1 Gene And Achilles Tendinopathy: A study found that variants within the MMP3 gene are associated with Achilles tendinopathy, and possible interactions exist with the COL5A1 gene.
  • Tenascin-C Gene And Achilles Tendon Injuries: A study found that the guanine-thymine dinucleotide repeat polymorphism within the tenascin-C gene is associated with achilles tendon injuries..
  • The COL1A1 Gene And Acute Soft Tissue Ruptures: A study summarizes these findings this way, "Three studies have suggested that the rare TT genotype of the functional Sp1 binding site polymorphism within intron 1 of COL1A1 is associated with cruciate ligament ruptures, shoulder dislocations, and/or Achilles tendon ruptures."