Tendinosis causes and treatments

[Samson]

It's a bit of a long read but I never knew there two types if tendon injuries.
It helped explain which type I had and the best way to treat it.
Hope you enjoy it.

What is Tendinosis?

Tendons are rope-like structures that attach muscles to bones. Ligaments are similar structures that attach bones to other bones. When muscles and bones move, they exert stresses on the tendons and ligaments that are attached to them.

When your muscles move in new ways or do more work than they can handle, your muscles and tendons can sustain some damage on a cellular scale. If the increase in demand is made gradually, muscle and tendon tissues will usually heal, build in strength, and adapt to new loads. Athletes use these principles to build muscle and tendon strength with good training programs.

You can, however, do some activity that injures a tendon on a microscopic scale and then do more injury before the tendon heals. If you continue the injurious activity, you will gradually accumulate these microinjuries. When enough injury accumulates, you'll feel pain. This kind of injury that comes on slowly with time and persists is a chronic injury; acute tendon injuries are sudden tears that cause immediate pain and obvious symptoms. Tendon injuries often require patience and careful rehabilitation because tendons heal more slowly than muscles do.

Tendinosis is an accumulation over time of small-scale injuries that don't heal properly; it is a chronic injury of failed healing. Although you can't see the tendinosis injury on the outside of your body, researchers have seen what the injury looks like on the cellular scale by viewing slides of tendons under the microscope. (The microscopic changes in the tendon are described on the page The Tendinosis Injury, and the difference between tendinosis and tendinitis is described below in the section on terminology.) Tendinosis can occur in many different tendons, with some of the most common areas being the hand, wrist, forearm, elbow, shoulder, knee, and heel.

Who Is At Risk For Tendinosis?

The Bureau of Labor Statistics recorded 44,504 injuries from tendinosis and/or carpal tunnel syndrome in U.S. private industry in 1999. This number translates to about one out of every two thousand full-time private industry workers in that year. Each year, tens of thousands more U.S. workers develop these injuries. For details, see Scope of the Problem .
Tendinosis can result from long hours of activities such as playing sports, using computers, playing musical instruments, or doing manual labor. It can result from activities performed as part of your profession or recreation. Some occupations that have increased risk for chronic tendon injuries include assembly line workers, mail sorters, computer programmers, writers, court recorders, data entry processors, sign language interpreters, cashiers, professional athletes, and musicians.

Minimizing Your Risk

You can minimize your risk for tendinosis by using equipment that has good ergonomic design and is sized correctly for your body, by using good technique for your activity (whether it is sports or music or typing), by taking plenty of breaks, and by minimizing long overtime hours (easier said than done!). You can also listen to your body's pain signals. Warning signs of tendinosis include burning, stinging, aching, tenderness to the touch, and stiffness.

Usually tendinosis sneaks up on you. At first the pain only comes after a long or hard session of the activity that aggravates it. Later the pain comes at lower levels of the activity and it lasts longer. Finally, the pain becomes a part of your daily life and even normal activities can make it worse. Try to catch the injury as early as you can.

Terminology: RSI, CTD, and Tendinosis vs. Tendinitis

Let's get some terminology out of the way. Repetitive strain injury or RSI is a term commonly used to refer to many kinds of injuries that are caused by repetitive motion. RSI includes things like tendinosis, carpal tunnel syndrome, thoracic outlet syndrome, trigger finger, and de Quervain's syndrome. Another term that is commonly used interchangeably with RSI is cumulative trauma disorder or CTD. These injuries are also collectively referred to as "overuse injuries." The terms RSI and CTD usually refer to workplace injuries, whereas the term overuse injury is also commonly used for sports injuries.

The terms tendinitis, tendinosis, and tendinopathy all refer to tendon injuries. These terms are commonly confused and misused. The term paratenonitis refers to an injury of the outer layer of tendon; this newer term replaces the older terms peritendinitis, tenosynovitis, and tenovaginitis.

tendinitis
The suffix "itis" means inflammation. The term tendinitis should be reserved for tendon injuries that involve larger-scale acute injuries accompanied by inflammation. (Tendinitis is often misspelled as tendonitis, but the preferred spelling used in most of the medical literature is tendinitis.)
tendinosis
The suffix "osis" implies a pathology of chronic degeneration without inflammation. Doctors prefer the term tendinosis for the kind of chronic tendon injuries that most of us have. The main problem for someone with tendinosis is failed healing, not inflammation; tendinosis is an accumulation over time of microscopic injuries that don't heal properly. Although inflammation can be involved in the initial stages of the injury, it is the inability of the tendon to heal that perpetuates the pain and disability. Most of the pain associated with tendinosis probably comes not from inflammation but from other irritating biochemical substances associated with the injury (see The Pain of Tendinosis and Overuse Tendon Injuries: Where Does The Pain Come From? for more information).[42]
tendinopathy
The suffix "opathy" implies no specific type of pathology, so the term tendinopathy is more general than either tendinitis (inflammation) or tendinosis (failed healing). The term tendinopathy just means tendon injury, without specifying the type of injury.
paratenonitis (peritendinitis, tenosynovitis, tenovaginitis)
These terms all refer to injuries of the outer layers of tendons. Tendons are enclosed in a connective tissue covering called the epitenon, which contains the vascular, lymphatic, and nerve supply. The epitenon is surrounded by another connective tissue covering called the paratenon, which in some tendons is lined by synovial cells. The paratenon and epitenon together are called the peritendon. Paratenonitis is inflammation and degeneration of the outer layer of the tendon, the paratenon, regardless of whether the paratenon is lined by synovium. Paratenonitis is a general term that is now preferred to the older terms peritendinitis, tenosynovitis, and tenovaginitis. De Quervain's syndrome is one example of paratenonitis. Tendinosis and paratenonitis can occur separately or together (that is, you can have both degeneration of the tendon itself, tendinosis, and degeneration/inflammation of the tendon sheath, paratenonitis).
For a longer discussion of these terms, see the article "Overuse Tendinosis, Not Tendinitis" on the website The Physician and Sport Medicine .[41,45]

The Need For Better Treatments

Once people get tendinosis, it usually becomes a long-term chronic problem with no easy solution. Many people have to change careers because they can't get their injuries to heal well enough to go back to their jobs, even if they make ergonomic improvements. They also have to make long-term changes to their daily lives outside of work to accommodate the limitations caused by the injuries. When tendinosis in an upper extremity is at its worst, people often have trouble performing even the simplest daily tasks such as opening doors, brushing teeth, shampooing hair, cutting and stirring food, tying shoes, turning pages of books and magazines, picking up children, and writing checks.

We need more research to find effective treatments for tendinosis; we don't understand why tendons often fail to heal even after the injurious activity is stopped, and we don't know how to reverse the damage. No current treatment has been proven to reverse the microinjuries associated with tendinosis. The injuries usually improve with time, rest, and physical therapy (and also with some nontraditional treatments), but no treatment has been shown to reverse the damage on the cellular scale. We could help many people if we could find a treatment that consistently reversed tendinosis injuries.

Some companies and researchers are already working on new ways to repair tendon injuries, and these new technologies could lead to better treatments for tendinosis (see Future Treatments ). With more funding, this research would progress faster.

Funding For Research

Many organizations provide information on how to prevent repetitive strain injuries, and they provide support for people who already have these injuries. However, I'm not aware of any group that exists to fund research into repetitive strain injuries. I'm hoping someday we'll have a nonprofit organization to fund research into RSI and tendinosis.

 

[Samson]

Continued

Future Treatments

Researchers have begun to investigate how to improve the slow, poor healing process of injured tendons and ligaments. Many of the experiments have been done on acute surgically-induced injuries, but the research should help develop techniques for chronic injuries as well.

I've given some examples of studies done on the various treatments listed below. My discussion is not meant to be an exhaustive review of the literature, but this sampling should give you an idea of the possibilities for future tendinosis treatments. Email me if you have research you think I should add to this section (be sure to give me references to the relevant journal articles published in the medical literature).

Note: The numbers in brackets after some sentences on this page are references found on the References page.

Local Injection of Stem Cells

Stem cells are progenitor cells found in embryos and also in some tissues of adults; these special cells can differentiate into cells for many different kinds of tissue such as bone, fat, cartilage, tendon, nerve, blood, brain, or muscle. Embryonic stem cells can differentiate into more tissue types than adult stem cells, but adult cells are more available and avoid the ethical and political issues associated with the use of embryonic cells. Adult stem cells have been found in many parts of the body, for example in fat, bone marrow, and skin.

One kind of stem cell is the mesenchymal stem cell or MSC; this type of cell can differentiate into various kinds of connective tissue. Adult bone marrow is one source for MSCs. Researchers are exploring how to use MSCs to repair tissues such as bone, tendon, ligament, and cartilage.[47]

Osiris Therapeutics Inc. is a small, private company in Baltimore, Maryland that is developing methods to use MSCs from adult bone marrow to treat injuries and diseases. Osiris can take a small number of MSCs and culture them to grow into large numbers of cells; then the cells can be directed to differentiate into cells for tendon, cartilage, bone, bone stroma, or muscle. Osiris is working on products to treat bone fractures, to treat patients who need to regrow bone marrow, and to create new heart tissue after heart attacks. Osiris is also investigating using the MSCs to treat osteoarthritis, cartilage injuries, and tendon/ligament injuries.

In several tendon studies, Osiris researchers surgically created one-centimeter-long gap defects in rabbit tendons and then implanted composites of stem cells suspended in Type I collagen gel into the injuries.[2,3,15] In one study, the MSC treated tendons were twice as strong as the untreated tendons after 4, 8, and 12 weeks.[15] The treated tendons also had larger cross-sectional area and better aligned collagen fibers. The authors concluded, "The results indicate that delivering mesenchymal stem cell-contracted, organized collagen implants to large tendon defects can significantly improve the biomechanics, structure and probably the function of tendon after injury."[15]

The researchers used autologous cells for this study (cells from the rabbits in the experiment), but Osiris has discovered that MSCs don't seem to provoke an immune response. Therefore, donors of MSCs do not need to be matched to recipients. Many researchers hope that we can develop a storage bank of MSCs that could be used to treat various injuries and diseases.

Although the Osiris studies looked at acute surgically-created tendon injuries, this research could be extended to look at chronic tendon injuries. Instead of surgically implanting MSCs into tendon gaps, MSCs could be injected directly into the area of chronic injury. The MSCs would be healthy cells uninjured by repetitive motion, and they could go to work creating new healthy collagen to slowly repair the area of failed healing.

One of the beauties of stem cell treatment for tendinosis is that it could be helpful under many of the scenarios postulated for the failed healing response (see Possible Reasons for the Failed Healing of Tendinosis). If the failed healing was caused by fibroblasts that were damaged by growth factors (or something else) associated with the repetitive motion, the new healthy cells would not have this damage and could heal the injury. For example, if the repetitive motion caused the fibroblasts to react abnormally to growth factors or to produce abnormal levels of proteolytic enzymes, the injected MSCs would provide some new cells with normal healing behavior. If the failed healing was caused by an abnormality in the genes of the fibroblasts, the MSCs could be taken from a donor who does not have that abnormality. In cases where the patient had genetically weaker tendons to start with, perhaps from a high Type III/Type I collagen ratio, stem cells taken from a donor without tendinosis would produce normal tendon collagen that might be stronger than the patient had originally.

Stem cell treatments would not make people immune to tendinosis, nor would they provide instant healing. They might, however, provide a way to get the tendon to heal with better collagen so that people could return to the way they were before the injury. Stem cells might be able to get the tendon out of its cycle of failed healing. Even though the healing would still take time, the end result might be tendon that would be much closer to normal uninjured tendon.

Stem cell treatments look very promising for acute and chronic tendon injuries; companies like Osiris need more funding to complete this research more quickly. Osiris put its tendon research on hold and is now concentrating on other products that are closer to being marketable. Osiris did have a $750,000 grant from the NIH for the tendon/ligament studies, but that grant was made several years ago and has been depleted.

If you're interested in trying to help this research move forward, please email me . I'm hoping we can speed up the process by finding funding that is specifically targeted for researching stem cell treatments for chronic tendon injuries.

Manipulating Growth Factors

Growth factors are proteins that stimulate cell proliferation and differentiation. Some growth factors can cause normal uninjured tendon fibroblasts to proliferate and synthesize more collagen and proteoglycans. Since growth factors play an important role in tissue healing, researchers have wondered if they could be used to improve the healing of tendons and ligaments.

Research into growth factor treatments is difficult because the effects of growth factors can be very different in vivo than in vitro and because fibroblast cells injured by repetitive motion can react differently to growth factors than normal cells. [1] In a study of carpal tunnel syndrome, wrist ligament cells from injured and uninjured people were exposed to four growth factors, including transforming growth factor beta (TGF-beta).[1] The cells from the 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 the controls. The cells in the injured patients seemed to have been altered by the injury so that their response to growth factors was different. Therefore, studies that use growth factors to improve healing of acute tendon injuries might not apply to healing of tendinosis injuries.

Nevertheless, growth factors are worth studying to determine their potential for treating acute tendon and ligament injuries and to see if any of the growth factors have positive effects on repetitive motion injuries as well. If growth factor treatments don't seem to produce a good response from cells injured by repetitive motion, stem cell treatment could be combined with growth factor treatment; the stem cells would provide normal uninjured cells for the growth factors to stimulate, and the growth factors could stimulate them to produce healthy tendon/ligament collagen. See the previous section "Local Injection of Stem Cells" for more information about stem cells.

Another obstacle with growth factor therapy is that a fine line could exist between too little and too much of the growth factor; too little could cause inability to heal and too much could cause abnormal healing, scar formation, or other negative effects. When wounds and acute injuries heal normally, the body provides the correct balance of growth factors at the correct time in sequence as healing progresses from one stage to the next. More research is needed to investigate whether we can control the timing and the amount of added growth factors well enough to optimize healing. Researchers will need to investigate how the effects of various growth factors depend on the dose, the injury site, the stage in the healing process, and the interactions with other growth factors.

Various delivery methods for growth factors have been tried. Growth factors can be injected directly into the site of injury, but they tend to break down quickly. Researchers have had difficulty maintaining constant enough levels with the injection method. Other researchers have tried implanting controlled-release polymer matrices or microspheres into the injury site to slowly release growth factors into the tissue; these methods could be appropriate for some acute injuries, but a non-surgical method is better for tendinosis. Many researchers are now looking toward gene therapy delivery methods as being the most promising way to use growth factors to improve healing of injuries. See the section below on "Gene Therapy."

The following list of growth factors describes some of the studies that have been done to determine whether these substances can be used to help improve the healing of tendon and ligament injuries.

IGF-1
Insulin-like growth factor 1, or IGF-1, is a growth factor that is important for tissue healing. It can stimulate an increase in Type I collagen when added to normal fibroblasts.

One study showed that tenocytes from healthy equine tendon made more Type I collagen relative to Type III collagen when treated with IFG-1 in vitro.[31] The tendon samples had "greater numbers of larger and more metabolically active fibroblasts," and IGF-1 enhanced collagen synthesis in a dose dependant manner. The authors suggest that IGF-1 might help treat horses with tendinosis. A growth factor that helps promote Type I collagen relative to Type III collagen in tendon is certainly worth more study for its potential use in treating tendinosis.

Several other studies showed that a combination of IGF-1 and platlet-derived growth factor increased the rupture force, stiffness, and breaking energy in rat medial collateral ligaments.[32,33] Also, one study showed that treating injured rat Achilles tendons with IGF-1 reduced the "maximal functional deficit" and the "time to functional recovery."[34] Another study showed that IGF-1 and IGF-II stimulated collagen, proteoglycan, and DNA synthesis in a dose-dependent manner in rabbit flexor tendon in vitro.[35]

IGF-1 was not one of the growth factors tried in the previously mentioned carpal tunnel syndrome study[1], so it would be interesting to discover its effect on cells from tendinosis patients.
GDF-5
Growth and differentiation factor 5, or GDF-5, has been linked to tendon healing in several studies. One study showed that the tensile strength of healing rat tendons increased in a dose-dependent manner when treated with GDF-5.[36] Another study showed that GDF-5 deficiency caused mouse tail tendon to have a 17% increase in the proportion of medium diameter collagen fibrils at the expense of larger diameter fibrils, as well as a 33% increase in irregularly-shaped polymorphic fibrils.[37] These structural differences did not cause major differences in biomechanical properties of the tendon, but did cause the fibers to relax 11% more slowly than controls during time-dependent stress/relaxation tests. More research would be needed to see if GDF-5 could play a role in the treatment of tendinosis.
CDMP-2
One research group has investigated the potential for treating tendon injuries with cartilage derived morphogenetic protein, or CDMP-2.[25] This protein is a member of the TGF-beta super family. The researchers treated injured rat Achilles tendons with injections of CDMP-2 and found that the treated tendons were 39% stronger than controls after 8 days. The tendons were also mechanically loaded during healing because the researchers suspected that loading would help the CDMP-2 induce tendon-like tissue instead of bone or cartilage tissue. (The abstract didn't say if the control tendons were also mechanically loaded; if not, the improved healing could be from the loading rather than from the CDMP-2. Presumably, they loaded both the controls and the treated injuries.)
TGF-beta1
Transforming growth factor beta1, or TGF-beta1, is a growth factor important in wound and tissue healing. It has been associated with excessive scar tissue formation in some cases. A group of researchers studied the effect of reducing TGF-beta1 because they were looking for a way to reduce the adhesions and scar tissue that commonly form between the site of injured hand flexor tendon and the surrounding tissues.[26,27] These adhesions reduce normal range of motion. Injured rabbit flexor tendons treated with neutralizing antibody to TGF-beta1 had approximately twice as much range of motion as the controls after 8 weeks of healing. This research might not have direct implications for treating tendinosis, but it does show that sometimes lowering growth factors can lead to better healing; more is not always better when it comes to growth factors.
BMP-12
Bone morphogenic protein 12, or BMP-12, has been shown to improve tendon healing; researchers found that in vivo gene therapy delivery of BMP-12 caused a two-fold increase in tissue strength and stiffness of healing chicken tendons.[38] See the section below "Gene Therapy."
Gene Therapy

The science of gene therapy is in its early stages, but it holds promise for treating all sorts of diseases and injuries. Gene therapy involves delivering a desired gene into cells and tissues in the patient's body to achieve therapeutic results. It can mean replacing a defective gene, or adding a gene that will cause cells to make beneficial proteins, or adding a gene that will cause cells to make proteins that will block harmful proteins. When applied to the healing of injuries, gene therapy could deliver a gene that encodes for a protein that would enhance the healing process, such as a growth factor. This method is better than simply injecting the growth factor directly into the injury because delivery via gene therapy allows the level of the growth factor to be maintained for the long periods of time required for tissue healing.

One of the biggest challenges facing gene therapy researchers is finding a good way to carry the desired gene into the targeted cell. Various gene carriers, or "vectors," have been tried, including liposomes and disabled viruses. Liposomes or viruses can carry the gene into the targeted cells of the body, and then those cells use that DNA to make the protein the DNA encodes. Nonviral vectors such as liposomes are less efficient at transferring genes, so more research has been done with disabled viruses than with nonviral vectors.

The vectors can be injected systemically into the patient's bloodstream, or they can be delivered locally to the desired site. Local delivery can be accomplished in several ways. The vector can be injected directly into the site in vivo, or the vector can be introduced into cells in vitro and then the modified cells can be injected into the desired site. The cells that carry the gene can be the patient's own cells that are modified and then reinjected or they can be stem cells.[19] The in vitro vector method is safer than the in vivo method because the virus is not introduced directly into the patient's body.

Gene therapy has successfully delivered genes to tendon and ligament tissue.[20,21,22,23,24,38] Gene therapy could help people who are especially prone to tendinosis because of genetic differences; if we could identify the genetic abnormalities that were making some patients prone to tendinosis, we could fix the abnormalities. This kind of gene therapy that involves treating a genetic problem is a long-term ambitious goal, and it only addresses genetic causes of tendinosis. Another approach is to use gene therapy to modify the failed healing of tendinosis rather than some genetic defect in the individual.

One example of using gene therapy to improve tendon healing is a study in which researchers used the gene for a growth factor called bone morphogenic protein 12, or BMP-12, to improve healing of injured chicken tendon.[38] First, the researchers used a virus to transfer the BMP-12 gene into chicken tendon cells in vitro; following treatment, the tendon cells increased their synthesis of Type I collagen. Then the researchers transferred the gene into lacerated tendons of chickens in vivo and observed "a two-fold increase of tensile strength and stiffness of repaired tendons, indicating improved tendon healing in vivo." The gene therapy succeeded in transferring the gene to the site of injured tendon and succeeded in improving the healing process. To see whether this success could translate into a treatment for tendinosis, we'd need to investigate whether BMP-12 could help stimulate Type I collagen synthesis even in tendon injured by repetitive motion (possibly in combination with stem cell therapy).

Another study used gene therapy to improve the scar tissue that forms when injured ligaments heal.[24] The researchers injected antisense decorin oligodeoxynucleotides into injured rabbit ligament to down-regulate the proteoglycan decorin and improve the mechanical properties of the area after it healed. After 6 weeks, the treated ligaments showed an 83-85% improvement in strength compared to the untreated controls. However, the authors state in a supplementary article that "mRNA for multiple genes were affected by the decorin-specific antisense treatment and therefore all of the observed improvements in scar tissue cannot be directly ascribed to depressing decorin levels."[39] More research will be needed, but the gene therapy did have a positive effect on healing.

The authors of the decorin study stressed that they used a method of gene therapy that did not permanently alter the tissue; it only temporarily modulated some substances during the early stages of healing. Researchers are working on various ways for gene therapy to target specific sites of injury and be activated only for limited periods of time. For local tissue healing applications, gene therapy should not have permanent or systemic effects.

Gene therapy could be used to regulate various substances, such as growth factors and proteolytic enzymes, that affect the healing process in tendon. We need more research to determine which substances are most helpful and harmful to the tendinosis injury. After identifying the substances, gene therapy offers a method of delivering the substances or their inhibitors to the site of injury.

For more information about gene therapy, see "Gene Therapy and Tissue Engineering in Sports Medicine".[43]

Nitric Oxide Synthase

Nitric oxide synthase, or NOS, is an enzyme that reacts with L-arginine (an amino acid) to produce nitric oxide. Researchers found that the three NOS isoforms are up-regulated following tendon injury and that inhibiting NOS activity with oral drugs reduces the cross-sectional area and failure load of healing Achilles tendon in rats.[28,29,30] Further study showed that the three isoforms are expressed by fibroblasts "in a coordinated temporal sequence during tendon healing." [30] The authors of the third study suggest that each NOS isoform might play a different role in healing and that these substances might be able to be manipulated to achieve therapeutic effects.[30] Another question would be whether any of the NOS isoforms are somehow inhibited in the failed healing process of tendinosis. We don't know much about NOS's role in tendon healing yet, so its potential as a therapeutic agent is unknown.

 

[Samson]

More

The Tendinosis Injury

People have various images in their minds to represent their overuse injuries. Some people visualize their injuries as tissue that is stuck together by adhesions and needs to be loosened. Others imagine tendons that look like frayed ropes, hanging by their last threads. This section will help you understand the tendinosis injury a little better so you can replace vague and inaccurate mental images with more realistic information. You might have more patience to wait for your injury to heal if you understand why it heals so slowly and what's going on in there while you're waiting.

When you understand what the injury involves, you'll also be less vulnerable to people selling "cure-all" products that can't possibly live up to their promises (saying, for example, that some device or exercise or pill can cure your injury in less than a week). You'll also be more alert to new treatments that might really make a difference. Distinguishing between the two cases is not always easy, but the more information you have the better you can decide what's worth trying.

Note: The numbers in brackets after some sentences on this page are references found on the References page.

What Is Collagen?

Collagens are proteins that help strengthen the structure of tissues such as bones, tendons, cartilage, ligaments, vertebral disks, skin, and blood vessels. These tissues all contain collagen, but they have different proportions of different kinds of collagen (as well as various other constituents) and their structural characteristics vary.

The collagen in tendons and ligaments is arranged in bundles of parallel fibers, giving 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 cartilage is arranged in a mesh with a large amount of gel-like substance between the collagen fibers, making the structure of cartilage more like a sponge. The characteristics of collagen-containing tissues also vary with position within the structure; for example, tendons and ligaments are different at the point of insertion to the bone than they are in the middle of the tendon or ligament.

Researchers have identified 19 kinds of collagen and given them names with Roman numerals. The main collagens found in connective tissue are Types I, II, and III; these collagens form fibers that give tensile strength to tissues. Tendons, ligaments, skin, and bone have mostly Type I collagen, and cartilage has mostly Type II collagen.

Tendons and ligaments also contain proteoglycans, elastin, and fibroblast cells. The collagen, elastin, and proteoglycans form the extracellular matrix. The fibroblast cells are embedded in the matrix and in fact 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 new tendon tissue is being formed, the fibroblasts are actively creating new collagen. 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. Fibroblasts tend to look thicker, rounder, and larger than fibrocytes, which tend to look thinner and more linear. 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.

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.

The collagen fibers in tendons are arranged in primary, secondary, and tertiary bundles within a sheath called the epitenon that surrounds the exterior surface of the tendon. To see a schematic diagram of this tendon structure, see Figure 1 in Histopathology of Common Tendinopathies by Khan et al.[18]

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 (with abnormal quantity or quality), leading to weak tissue and various collagen diseases.

Abnormal Collagen in Tendinosis

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

Usually you can't see the tendinosis injury from the outside of the body; swelling, heat, and redness are symptoms of an acute injury, not a chronic tendinosis injury. However, the tissue often looks different to the naked eye during surgery, with tendinosis showing up as tendon that looks 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:

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.
Inflammatory cells are usually not seen in the tendon but sometimes are seen in the synovium and peritendinous structures (the areas around the tendon).
Electronic microscopic observations have shown alterations in the size and shape of mitochondria in the nuclei of the tenocytes.
To see many interesting photographs of microscope slides, see the article "Cell-Matrix Response in Tendon Injury" by Leadbetter.[7] To see one online photo of a microscope slide, see the article "Overuse Tendinosis, Not Tendinitis" on the website The Physician and Sport Medicine .[41] A few more online photos are available in the article Overuse Tendon Injuries: Where Does The Pain Come From? [42]

The above changes have all been observed in tendon samples taken from sites of tendinosis. Researchers have also taken tenocytes (the tendon cells that make new collagen) from sites of tendinosis and cultured them. The tenocytes cultured from tendinosis 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).

The Tendinosis Cycle

The tendinosis 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. Part of the problem is that 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, tendinosis 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 tendinosis don't completely heal from it and can't go back to their previous level of activity. Once the tendinosis cycle starts, the tendon rarely heals back to its pre-injury state.

Although rest is an essential part of the healing process for tendinosis, 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; see Current Treatments .


The Pain From Tendinosis

The source of pain from tendinosis is controversial. At first, doctors labeled chronic tendon injuries as "tendinitis" and attributed the pain to inflammation. Later, doctors discovered that inflammatory cells were rarely seen in microscope slides of chronic tendon injuries. Therefore, many doctors have switched to the term "tendinosis" and have started to develop alternative theories about the source of pain.

The pain from tendinosis probably comes partly from the physical injury itself (separation of collagen fibers and mechanical disruption of tissue) and partly from irritating non-inflammatory biochemical substances that are produced as part of the injury process. The biochemical substances probably irritate the pain receptors in the tendon and surrounding area. NSAIDs and cortisone injections might reduce the pain of tendinosis by reducing or blocking these biochemical substances, rather than by reducing inflammation. See Overuse Tendon Injuries: Where Does The Pain Come From? for more information.[42]

Some people find that when the tendinosis in their wrists has an especially bad flare-up, they experience tingling or numbness in some fingers (carpal tunnel symptoms). The old explanation for the numbness was that severe flare-ups cause inflammation that presses on the nerves to the fingers and causes numbness. When the flare-up subsides, the numbness goes away. The newer theory is that the tendinosis injury causes thickening of the tendons in the wrists (partly from higher water content associated with the higher proteoglycan content), and this thickening can cause pressure on nerves to the fingers. Despite the larger cross-sectional area, tendons with tendinosis are still weaker than healthy tendons because of the structural abnormalities described in the previous sections. In addition to thickening of the tendon, inflammation of the tendon sheath can also put pressure on nerves to the fingers. Although the tendons and ligaments themselves don't usually show inflammation, the surrounding tissue sometimes does.

Risk Factors For Tendinosis

Tendinosis is a chronic degenerative tendon injury that is usually brought on by repetitive motion. The repetitive motion is often associated with activities in the workplace or with sports. Microinjuries gradually accumulate faster than they can heal until the area eventually becomes painful. The severity of the injury is influenced by many factors, including
the amount of overuse and lack of recovery time (for example hours of typing per day, per week, and per month as well as number of breaks per day)
the person's genetics (for example anything that makes the tendons more prone to injury, such as a higher initial Type III/Type I collagen ratio in the tendons)
the ergonomics associated with the repetitive motion activity (such as awkward position, tools that cause vibration, improperly fitted tools or sports equipment, or poor technique)
the person's age, level of fitness, and general health (chronic tendon degeneration is more common with age, and poor fitness makes sports injuries much more common)
the length of time the condition persists before the person seeks help and limits the activities that cause pain (this is often influenced by the person's awareness of RSI and the pressure the person feels to continue the injurious activity)
the quality of medical care/advice that is received
Varying Susceptibility To Tendinosis

People seem to vary in their susceptibility to tendinosis. Many people go through their entire lives without ever experiencing tendinosis. Some people experience mild tendon problems but recover. Others get chronic tendinosis from obvious overuse such as typing or sports. A few unlucky people get chronic tendon injuries in multiple places of the body, sometimes without obvious overuse. (Leadbetter refers to this propensity for tendinosis as mesenchymal syndrome.[7]) Even given the same ergonomics, different people have different levels of activity that constitute injury-producing overuse; the line between use and overuse varies with genetics.

Any genetic variant that causes tendons to be weaker or slower to heal could make people more susceptible to tendinosis. For example, some people might have a genetic reason for a higher than normal Type III/Type I collagen ratio in their tendons. If we can understand the reasons for differences in susceptibility, we might find better treatments for tendinosis.


Possible Reasons For the Failed Healing of Tendinosis

More research is needed, but this list gives some of the possible explanations researchers have suggested for the abnormal collagen production associated with chronic overuse injuries.

The Poor Intrinsic Healing Capability of Tendons
Tendons and ligaments don't heal well, 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.
Long-Term Exposure to Growth Factors
Another possible explanation for the abnormal collagen associated with chronic overuse injuries is that the fibroblasts could be damaged by long-term exposure 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 the 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.

Growth factors have the potential to help tendons and ligaments heal, but sometimes they might actually hinder the process. We need more research to sort out the effects of various growth factors and to investigate whether they can be used as treatments to promote collagen healing in tendinosis. See Future Treatments . One complication for this research is that growth factors can have completely different effects on cells in the body than on cells in the petri dish. Another complication is that many studies look at acute surgically-induced injuries rather than chronic overuse injuries, and the effects of growth factors could be very different in these two cases.
Genetic Variants In Collagen
Another possibility is that some people with chronic overuse injuries could have genetic differences that make their tendons and ligaments weaker and make them heal with abnormal collagen. Quite possibly, more than one genetic variant exists that causes tendons and ligaments to be prone to overuse injuries.

Many genetic collagen defects have already been discovered; some cause fairly rare collagen diseases, but some cause more common problems like osteoporosis, osteoarthritis, and vertebral disk herniations. A colIA1 defect has recently 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 several observed collagen abnormalities that could contribute to the failed healing response of chronic overuse injuries. Perhaps we will soon discover the causes for these abnormalities.

Abnormal Alpha2(I) To Alpha1(I) Ratio
As mentioned in the section above "Abnormal Collagen in Tendinosis," one study found that the ligaments of carpal tunnel syndrome patients had abnormally high ratios of alpha2(I) to alpha1(I), just the opposite of the osteoporosis study.[1,10,12] Perhaps people who are susceptible to carpal tunnel syndrome have a collagen defect that causes this abnormal ratio, or perhaps the repetitive motion itself somehow brings about the altered ratio. The end result is probably weaker, abnormal collagen that is more prone to overuse injuries like carpal tunnel syndrome.

Abnormal Type III/Type I Ratio
The other collagen abnormality that has been associated with overuse injuries is a high Type III/Type I ratio.[1,6,9,13,14] Perhaps some people have a genetic reason for a higher Type III to Type I collagen ratio in their tendons and ligaments, and this makes 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; a genetic variant in collagen seems a likely explanation for these observations.[6,14]

Gender may also play a role in connective tissue strength. 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] See Scope of the Problem for some statistics on gender differences for RSI.

An abnormally high Type III/Type I ratio is a normal feature of the initial stages of tendon healing, but this ratio persists in tendinosis. 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 tendinosis because their tendons would be weaker. Once the tendinosis cycle starts, these people would develop even higher Type III/Type I ratios in the injured areas because that is how tendons heal. Perhaps these people develop more chronic cases of overuse injuries because they don't have any room to absorb the higher Type III/Type I ratio that automatically comes with injury. People with better initial Type III/Type I ratios might eventually heal to some threshold level that lets them function normally, but people with higher initial ratios might have a harder time reaching that threshold.

Genetics will probably turn out to be an important piece of the tendinosis puzzle. Only one small study looked at the alpha2(I) to alpha1(I) ratio, so it might not be significant.[1] Many studies of all kinds of overuse injuries have observed the abnormally high Type III/Type I ratio, so that observation is likely to be very significant.[1,6,9,13,14] Other collagen abnormalities might be discovered to be associated with overuse injuries as more research is done. To understand how genetic research might lead to better treatments for tendinosis, see Future Treatments .

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 tendinosis found that tendons with tendinosis had lower levels of MMP-3 mRNA than other tendons without tendinosis in the same patients.[16] Even more interesting, the "normal" tendons of patients with tendinosis had lower MMP-3 mRNA than tendons of control patients who had no tendinosis anywhere. This study implies that differences exist not only between tendons with and without tendinosis, but also between people who are and are not prone to tendinosis. Maybe people who are prone to tendinosis 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, but it does show that another factor to consider in the failed healing of tendinosis is the level of proteolytic enzymes available for tendon repair.

Of course too high a level of proteolytic enzymes can also be a problem. You don't want the tissue to be broken down by the body so quickly that normal remodeling efforts can't keep up. Tendinosis already involves an injury rate that exceeds the rate of repair, so you want to encourage the repair process and slow the injury rate. You need enough proteolytic enzymes to enable repair of injured tissue, but not so much proteolytic enzymes that uninjured tissue is broken down. Normally the body maintains a balance between proteolytic enzymes and their inhibitors to achieve a balance between tissue breakdown and repair.
These four explanations (the poor healing capacity of tendon, genetic variants in collagen, long-term exposure to growth factors, and abnormal levels of proteolytic enzymes) are just some of the possible reasons that have been suggested for the failed healing of collagen in tendinosis. More research is needed to fully understand the tendinosis Injury.

 

[extremevet]

I thought osis was smell related like Halitosis or vaginosis... learn something new every day.