Tendinopathy: The Inside Story
Learning about tendinopathy at the cellular level can help you understand your injury and evaluate possible treatments for it..
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 that help define their character.
A collagen protein is formed from three amino acid chains that are wound together into a triple helix. Amino acids are the building blocks of proteins. 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.
Tendon Structure
Schematic illustration showing a triple helix of amino acids in a collagen molecule that is bundled into a tendon fibril that is bundled into a larger tendon fiber.
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 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 or tenocytes. The tenocytes don't actively create new tissue unless they are called on to repair damage or do remodeling of the old tissue.
A typical collagen molecule consists of three subunits called alpha chains that are composed of combinations of amino acids. Since it is composed of three alpha chains, the collagen molecule is called a tripeptide. The most abundant amino acids in collagen are glycine, proline, and lysine.
The Types Of Collagen
Scientists have categorized collagen into at least 16 different types, usually referred to with Roman numerals. Three types are mainly of interest when talking about tendons and connective tissue.
Type I: Type I collagen is the most abundant collagen in the body and is found in skin, tendon, ligaments, bone, hair, nails, organs, eyes, and other connective tissue. It is the main collagen type in tendons.
Type II: Type II collagen is mainly found in cartilage, as well as in parts of the eyes and vertebral disks.
Type III: Type III collagen is found in blood vessels, the uterus, the bowel, and in reticular structures such as in bone marrow. Small amounts are also found in tendons.
Collagen Peptides: You might have seen or purchased collagen peptides as a supplement to try to help improve your skin, tendons, or joints. The peptides are broken down pieces of amino acid chains that make up collagen molecules. Peptides have interesting properties in that they can serve as messengers in the body, telling the body to take some action. So in addition to serving as raw building blocks of collagen, certain peptides might also be able to message your body to repair skin or tendon. Type I collagen peptides from bovine or marine sources are commonly used in supplements targeted for tendon and skin, and Type III collagen peptides from chickens are commonly used in supplements targeted for the cartilage in joints.
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.
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 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 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.
- 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. More recent studies have found abnormal chromatin in tendinopathic 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 develop chronic overuse injuries of failed healing. Ligaments with overuse injuries show the same kinds of abnormal appearance under the microscope as tendons with tendinopathy. 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 tendinopathy. [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).
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.
