Why Failed Healing?
Researchers are trying to understand what goes wrong in tendinopathy and how to fix it. This page describes the tendinopathy cycle and some abnormalities associated with tendinopathy that contribute to the failed healing.
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. The new collagen fibers are less organized into the normal parallel structure, which also makes the tendon weaker.
Therefore, tendinopathy is a slow accumulation of little injuries that are not repaired properly, leaving 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.
Although rest is an essential part of the healing process, too much rest causes deconditioning of muscles and tendons. Weaker muscles and tendons leave the area more vulnerable to injury. In this way, the area becomes weaker on a large scale as well as on a cellular scale. This cycle of injury/rest/deconditioning/re-injury can be difficult to break. Gradual, careful physical therapy exercises can help.
Abnormal Chromatin In Tenocytes
One possible reason for the failed healing in tendinopathy relates to the chromatin in tenocyte cells (chromatin is a mixture of DNA and protein in the nucleus of cells). A study released in August 2022 found that the chromatin in tendinopathic tenocytes was disorganized and unable to function correctly or to reorganize itself to repair the damage. This discovery not only gives us a better understanding of the injury, but it also suggests possible new treatments with small-molecule therapy. This is an area to watch in the future. For more information, see our blog post on the Research News page.
Abnormal Type I To Type III Collagen Ratio
Tendons and ligaments heal slowly, 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] Researchers have hypothesized that part of the reason for the slow healing is because tendons have less blood supply than muscles, and another contributing factor is that tendons heal by first laying down more Type III collagen than is found in uninjured tendon.
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] 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.
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, mice, and horses. A human trial is now underway. For more information, see our blog post on the Research News page.
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. For more discussion of this study, see our blog post on the Research News page.
Altered Growth Factor Response
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 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.
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 result in collagen disorders, such as Ehlers-Danlos Syndrome, that cause tendons to be more easily injured. Some defects in collagen genes 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 has an association with chronic Achilles tendinopathy. Individuals with an A2 allele of this gene had lower risk of developing Achilles tendinopathy.
MMP3 Gene 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 in the British Journal of Sports Medicine found a genotype associated with the COL1A1 gene that seems protective against some specific tendon and ligament injuries such as cruciate ligament and Achilles tendon ruptures. The study says that "the rare TT genotype of the functional Sp1 binding site polymorphism within intron 1 of COL1A1" seems to be protective against acute soft tissue ruptures and "should be incorporated into multifactorial models determining risk of acute soft tissue ruptures."
