Chronic Tendon Injury: The Inside Story

This page presents what we know about chronic tendon injuries on a cellular level inside your body.

What Is Collagen?

Collagen is a protein that helps strengthen the structure of tissues such as bones, tendons, cartilage, ligaments, vertebral disks, skin, and blood vessels. These tissues contain different types of collagen (as well as other constituents), and their structural characteristics vary.

A collagen protein is formed from three polypeptide chains, also called amino acids, wound together into a triple helix. In tendons, collagen triple helices bundle together into fibrils, which themselves bundle together into strong fibers. The whole tendon structure is covered by a loose sheath called the epitenon that contains the vascular, nerve, and lymphatic supplies.

The bundles of parallel fibers gives tendons and ligaments a rope-like structure. Some of the fibers in tendons and ligaments also run transverse to the parallel bundles, forming cross-links that add strength to the structure. The collagen in tendons and ligaments is different at the point of insertion to the bone than it is in the middle of the tendon or ligament.

Collagen structure showing amino acid chains and how they combine into a collagen molecule and collagen fibers.

Tendon Structure

Tendons and ligaments contain collagen, proteoglycans, elastin, and fibroblast cells. The collagen, elastin, and proteoglycans form the extracellular matrix. The fibroblast cells are embedded in the matrix and synthesize and secrete the matrix collagen, elastin, and proteoglycans.

The proteoglycans are protein/polysaccharide complexes that trap water and affect the viscoelastic properties of the tissue, helping the tissue resist compressive forces. Proteoglycans consist of a protein core with attached glycosaminoglycans (GAGs). Cartilage contains a high percent of a mixture of proteoglycans and water that provides a gel-like cushioning for joints. Tendons contain less proteoglycans and water than cartilage. The proteoglycan/water component of tendon, ligament, and cartilage is called the "ground substance."

The elastin fibers, which can stretch and return to their original form, are interwoven with the collagen fibers to add elasticity and prevent tearing. The elastin fibers form a network throughout the tissue, but they only represent 1-2% of the dry weight of tendon. Collagen represents 65-80% of the dry weight of tendon and is by far the most abundant component of tendon.

When they are young, fibroblasts are actively creating new collagen, but when the tissue is mature, the fibroblasts become less active and are called fibrocytes. The fibrocytes don't actively create new tissue unless they are called on to repair damage or do remodeling of the old tissue. Fibrocytes found in tendons are called tenocytes. (Likewise, fibrocytes found in cartilage are called chondrocytes and fibrocytes found in bone are called osteocytes.)

A typical collagen molecule consists of three subunits called alpha chains. For example, each molecule of Type I collagen has two alpha1 chains and one alpha2 chain. Each molecule of Type III collagen has three alpha1 chains. Since it is composed of three alpha chains, the collagen molecule is called a tripeptide. The alpha chains are composed of combinations of amino acids, which are the basic building blocks of proteins. The most abundant amino acids in collagen are glycine, proline, and lysine.

The Making Of Collagen

Procollagen: Type I, II, and III collagens are made in several steps. First, the fibroblast cell joins three alpha chains to make procollagen according to the instructions in the genes. Then, the procollagen is released from the cell membrane. The fibroblast cells secrete enzymes that remove extra sequences at the ends of the procollagen to make tropocollagen. Then the tropocollagen assembles into collagen fibrils, which then assemble into collagen fibers.

Illustration showing collagen structure with fibers arranged in bundles.

How Genes Control The Making of Collagen: Researchers have identified at least 30 collagen genes, and most of them encode procollagens. For example, the colIA1 gene encodes the alpha1 chain for Type I collagen, known as alpha1(I), and the colIA2 gene encodes the alpha2 chain for Type I collagen, known as alpha2(I). Defects in the collagen genes can cause the collagen to be constructed incorrectly, leading to weak tissue and various collagen diseases.

Abnormal Collagen in Tendinopathy

Normal tendons and ligaments consist mostly of Type I collagen, with smaller amounts of Type III collagen.  When you develop tendinopathy, some of your collagen is injured and breaks down. Your body tries to heal the tendon, but it doesn't repair the collagen properly.

Usually you can't see the tendinosis/tendinopathy injury from the outside of the body; swelling, heat, and redness are symptoms of an acute injury, not a chronic tendon injury. The tissue often looks different to the naked eye during surgery though, with regions of tendinosis/tendinopathy looking dull, slightly brown, and soft instead of white, glistening, and firm. Researchers have analyzed samples of tendons and ligaments under the microscope to discover the abnormalities that occur on a cellular scale in overuse injuries.

Research has shown that chronic overuse injuries such as tendinosis (including Achilles, rotator cuff, lateral and medial elbow, posterior tibial, digital flexor, and patellar), as well as carpal tunnel syndrome and even TMJ disorders are associated with a failed healing response in which the body's fibroblasts produce abnormal tendon and ligament collagen. [1,4,5,6,7,8,9,13,14,18,40,42] The composition and structure of the collagen is abnormal compared to uninjured tendon and ligament tissue. The following differences have been observed:

Structure And Composition Changes In Tendinopathy

  • The total amount of collagen is decreased (since breakdown exceeds repair).
  • The amounts of proteoglycans and glycosaminoglycans are increased (possibly in response to increased compressive forces associated with the repetitive motion).
  • The ratio of Type III to Type I collagen is abnormally high.
  • The normal parallel bundled fiber structure is disturbed; the continuity of the collagen is lost with disorganized fiber structure and evidence of both collagen repair and collagen degeneration.
  • Microtears and collagen fiber separations are seen.  Many of the collagen fibers are thin, fragile, and separated from each other.
  • The number of fibroblast cells is increased; the tenocytes look different, with a more blast-like morphology (the cells look thicker, less linear).  These differences show that the cells are actively trying to repair the tissue.
  • The vascularity is increased.
  • Electronic microscopic observations have shown alterations in the size and shape of mitochondria in the nuclei of the tenocytes.
  • Early studies found that inflammatory cells were not usually seen in the tendon but were sometimes seen in the synovium and peritendinous structures (the areas around the tendon). More recent studies have found inflammatory cells in the tendon too.

These changes have all been observed in tendon samples taken from sites of tendinopathy.  Researchers have also taken tenocytes (the tendon cells that make new collagen) from sites of tendinopathy and cultured them.  The tenocytes cultured from tendinopathy continue to produce abnormal collagen outside of the body; the tenocytes produced collagen with abnormally high Type III to Type I ratios (as compared to collagen produced by tenocytes cultured from normal tendon). [9]  This observation is significant because it shows that the tenocytes have been altered and continue to produce abnormal collagen even when the repetitive motion is no longer present.

Tendons and ligaments are similar structures; tendons connect muscle to bone, and ligaments connect bone to bone.  Ligaments, as well as tendons, can get chronic overuse injuries of failed healing.  Ligaments with overuse injuries show the same kinds of abnormal appearance under the microscope as tendons with tendinosis. One study showed that cells from the flexor retinaculum ligament of carpal tunnel syndrome patients made collagen with an abnormally high Type III/Type I ratio just as has been observed with cells from tendons of patients with tendinosis. [1] The carpal tunnel study also found that the injured ligament cells made collagen with a higher than normal ratio of alpha2(I) to alpha1(I).

Musculoskeletal System

illustration of musculoskeletal system

This image depicts the musculoskeletal system with the connective tissue, including tendons and ligaments, in the white-ish color.

Inflammation In Tendinopathy

Initially, chronic tendon injuries were called tendinitis and attributed to inflammation from overuse. Later, lack of inflammation seen on the cellular scale led to a change in terminology, calling chronic tendon injuries tendinosis and reserving the term tendinitis for acute injuries accompanied by inflammation. More recently, the terminology changed again to tendinopathy to distance the name from the pathology since the mechanisms are not fully understood.

Recent studies have documented Inflammatory signs at the cellular level in tendinopathy. A blog post Tendons, Let’s Talk About Inflammation… on The Sports Physio blog summarizes the current thinking and links to some recent articles discussing the possible role of low level inflammation in tendinopathy. A 2017 article in the British Journal of Sports Medicine discusses "a complex inflammation signature" seen in chronic Achilles tendinopathy, and a 2013 article in the British Journal of Sports Medicine urges the medical community to acknowledge the existence of inflammatory cells in tendinopathy. Doctors are not saying that use of NSAIDS or cortisone is a cure or that their long-term use is a good idea, but researchers don’t want to overlook any clues to the pathology of the injury, which is still not completely understood.