Connective Tissue: The Good, The Bad and the Ugly by Elzi Volk

In Part I of this series, readers were introduced to basic histology and physiology of connective tissue. We learned that all connective tissue has similar components, although the proportions of these components vary. These variations impart the mechanical and biochemical attributes to specific connective tissue. To illustrate, mechanical properties of articular cartilage that allow it to absorb impact and resist wear are partially due to the large proteoglycan aggregates.

We also learned that each component of connective tissue is built up with modular pieces. Each of these molecular modules requires energy and catalysts, such as enzymes and cofactors, for every given reaction of synthesis. Therefore any alteration in the synthesis or degradation of a module will affect its ultimate constitution. When there are numerous altered modules, a domino effect may eventually modify the complex community of macromolecules and result in changed characteristics of a tissue.

Many modulators influence turnover of connective tissue components and tissue remodeling. Recall from Part 1 that these modulators may be growth factors, hormones, cytokines, enzymes, and basic building blocks such as amino acids and carbohydrates. When dietary constituents or pharmaceuticals alter normal function of these modulators, resulting modified mechanical and metabolic characteristics may impair the normal biomechanics of a given connective tissue.

Before examining the influences of nutrition and pharmaceuticals on connective tissue, three types of dense connective tissue that are most important to athletes will be briefly described. These three types are tendons, ligaments and articular cartilage. Details of biomechanics will not be examined except where physiologically relevant. Readers who are interested in learning more about biomechanics are referred to textbooks on the subject.

Skeletal muscle and tendons are distinct tissues. However, they function as one unit: the musculo-tendon unit. Tendons attach the muscle to bones and transmit force from the muscle to the bone. Connective tissue forms a network throughout the muscle. It surrounds the fibers, the bundles of fibers and wraps around the whole muscle. This connective tissue network is continuous through the muscle and into the tendon that inserts the bone. Although the entire framework is essential to the function of the musculo-tendon unit, the tendon will be the focus of this discussion.

Tendons primarily consist of collagen � up to 85% of the dry weight � which imparts the mechanical and physiological properties of this tissue. Type I collagen predominates with small amounts (approximately 5%) of Type III and Type V collagen. Smaller amounts of elastin exist in the extracellular matrix. The type and quality of cross-linking varies in tendon fibers and is associated with the degree of mechanical loading experienced by the musculo-tendon unit. The regulation of the cross-link quality in new collagen is established by the mechanical loading during growth and development. Tendons that transmit the highest forces have the highest degree of cross-linking. Mechanical forces also determine morphology of collagen. The distal end of human tibialis posterior tendon, which receives compressive forces as well as tensional forces, exhibited less linear and more swirled collagen formation than seen in the proximal end (which receives mostly tensional forces).

Proteoglycans (PGs) in the tendon extracellular matrix are typically of two major classes that differ in structure and function. In general, the large cartilage-type proteoglycan monomers are present in low concentrations and the smaller dermatan sulfate proteoglycans (DS-PGs) are present in high concentrations. However, in tendons that are subject to compressive loads, the concentration of cartilage-type PGs is increased to impart special biomechanical properties to the tissues. The DS-PGs regulate the growth and size of the collagen fibrils during tendon development and repair.

Vogel et al (1) demonstrated morphological and PG heterogeniety in tendon and ligaments excised from human cadavers of various ages. Different cell shapes and concentration and type of glycosaminoglycans (GAGs) exist between the distal and proximal ends of tendons. Similar differences exist along the length and in the thickness of the tissues. The PG content of the tendon region that experiences compression and tensional forces (e.g. in the region of the tendon that passes under or around a bone) increases by as much as three times that of the tensional region. Increased concentration of large PG content may enhance a tissue�s compressive stiffness.

The closely packed fibers are bundled together and run parallel to the long axis of the tendon. Fibroblasts are few and located in the spaces between the collagen bundles. Many collagen bundles grouped together form the fascicle, and a synovial-like membrane, the epitenon, surrounds several fascicles to form the tendon unit. This membrane contains blood and lymphatic vessels and nerves. Several layers of elastic connective tissue sheaths enclose the tendon unit. The properties of these layers vary depending on site. Some tendons (such as the flexor tendons in forearm) are enclosed by a synovial sheath which carries many blood vessels.

The nerve supply to tendons and ligaments originates from the nerves of the muscles. Tendons are well vascularized: less than muscle and more than ligaments. Degree of vascularity differs depending on structure and site of the tissue. Blood vessels within the tendonous tissue are relatively sparse. Altered blood flow and consequent production or accumulation of soluble factors may modulate the type and amounts of PGs and collagen. The more vascularized tendons have blood vessels that infiltrate throughout the tendon from the outer connective sheath. The less vascular tendons have outer membranes that act as conduits of blood supply for the tendon fibers within. The other source of nutrition is diffusion from the synovial fluid which provides a significant supply of nutrients for many tendons. The tissues enclosing and surrounding the tendon provide a cellular and vascular component for healing and providing nutrition to the tissue within.

Ligaments are bands of connective tissue that bind bones to each other, crossing joints with wide ranges of motion as well as joints with little motion. Unlike tendons, both ends of ligaments insert into bone. The tissue may exist as fibrous bands, sheets or short thickened strips in joint capsules. Unlike previous assumptions, ligaments and tendons differ from each other in several ways. Collagen content is generally similar in tendons and ligaments. Type I collagen predominates (90%) with small amounts of type III (10%), which is more than tendons. Ligamentous collagen has more reducible cross-linking. The tightly packed bundles of collagen with many fibroblasts are aligned along the axis of tension.

As in tendons, site-specific structural and biochemical differences exist in ligaments due to different mechanical demands and the nutritional environment. The elastin content in ligaments varies depending on function. Most ligaments have less than 5% elastin. However, others have higher concentrations (up to 75%) imparting more elastic properties. Intraligamentous blood vessels are sparse. Therefore, mid-tissue nutrition relies greatly on diffusion from nearby blood vessels which lie parallel to the tissue and synovial fluid.

Many ligaments contain more GAGs than tendons. As well, ligaments contain the three major types of PGs (1): the small PGs, decorin and biglycan, and the larger PGs. The smaller PG, decorin, is the major type of PG in tendons. How these differences affect the tensile strength is not elucidated.

The nerve supply to ligaments is similar to that of tendons: primarily supplied from the nerves of the muscles acting on the joint. However, numerous free nerve endings in ligaments may moderate pain sensation.

More than tendons, most information on ligament injuries and repair are based on animal models where ligaments are partially or completely cut. Studies demonstrate the substantial differences in the site-specific repair process in ligaments as well as tendons. Animal models show varying healing capacities for various ligaments. Because ligaments are generally less vascularized than tendons, the healing and repair process takes much longer and, in some ligaments, may regress or disappear completely. Studies demonstrate that remodeled tissue never achieves normal characteristics nor a return to original mechanical properties. Mature repaired ligament tissue lacks the strength of normal ligaments: usually 50-70% of normal tensile strength (2).

The Vogel et al (1) study validated the use of animal tissue models to study the cellular mechanisms that cause site-specific changes in connective tissue morphology. While this may be true for normal adaptive responses, differences in metabolism may limit extrapolations to nutrition and pharmaceuticals. Human and animal studies confirm that the amount of PGs that accumulate in specific regions of tendons is directly correlated with compressive and tensional loads placed on the tissue.

A joint is a junction of two bones, holding them together while allowing for smooth movement against one another. The joint capsule and fibrous lining holds many components where the bone-ends meet. The synovial cavity, which is surrounded by a membrane, contains fluid that lubricates and nourishes the articular cartilage, the tissue that caps the ends of the bones.

In addition to supplying nutrients to cartilage, synovial fluid contains phygocytic cells that remove debris resulting from wear and tear in the joint capsule. The amount of fluid in the synovium varies depending on the size of the joint. The fluid is normally viscous when there is no joint movement; as movement increases, the fluid becomes less viscous.

Cartilage is a resilient material that absorbs shock and provides an elastic surface for smooth gliding of joints. Chondrocytes are embedded in the extracellular matrix comprised of type II collagen, proteoglycans and water. Cartilage lacks blood vessels, nerves and a lymphatic system. The cells must therefore rely on diffusion of nutrients through the extracellular matrix from the underlying bone or the synovial fluid. Damage to articular cartilage may be present long before it is noticed since these joints are non-innervated. Peripheral activation and sensitization of nerves during inflammation may elicit pain well after degenerative processes are stimulated.

The extracellular matrix is of great importance to the cartilage. Recall from Part I that collagen fibers and the ground substance make up the extracellular matrix. Collagen fibers and the glycoproteins comprise the fibrous web that anchors the chondrocytes within the matrix and provide tensile strength to cartilage. The fundamental component in the ground substance is the GAGs. The large proteoglycan aggregates described in Part I play an important role in maintaining optimal function of our joints.

In cartilage, the predominant GAGs are chondroitin sulfate and keratan sulfate. As was discussed in Part I, the PG monomers link to hyaluronic acid to form large aggregates. Recall that these large PGs are highly negatively charged, repelling one another and attracting water which makes up 80% of the wet weight of articular cartilage. These PGs provide the compressive strength to the joints. When the joint is loaded the matrix compresses and water is squeezed out of the matrix. When the compressive force is removed, the negatively charged GAGs reabsorb water. Also, the high content of GAGs in the synovial fluid provides lubrication minimizing wear between the two joints.

Considering the importance of the extracellular matrix to normal physiology and function of articular joints, any factor that increases the ratio of degradation to loss of matrix components will cause cartilage health to deteriorate. Alterations in cellular activity may also affect the turnover rate and remodeling process.

Most connective tissue injuries involve damage to the structural components of the tissue. In sports activities, injuries are classified into two types: acute and overuse injuries. Acute traumas occur from lacerations and partial or complete rupture of the tissue. These injuries heal by the repair process described in Part I. Overuse injuries, the most common category, result from chronic overloading or repetitive motion. The capacity of the tissue for repair greatly exceeds degradation and cellular metabolism is altered such that damage occurs at the cellular and structural levels.

Inflammation is the most prominent symptom of both types of injuries. As discussed in Part I, inflammation is a natural part of the healing process in any injury. However, chronic inflammation may lead to increased tissue degradation and impair the repair process. Indeed, chronic inflammation is a major factor in several connective tissue diseases, especially within articular joints. Pharmaceuticals are often used to manage or alleviate symptoms occurring with connective tissue inflammation. However, many of these exogenous substances may alter the healing and repair process.

Metabolic states, such as aging and diabetes, may also affect connective tissue health. Aging is often accompanied by a decline in joint function or general stiffness of the joints, and influences the nature and extent of the repair process in injured tissue. As connective tissues age, the composition of collagen and proteoglycans change which in turn alters the mechanical properties and physiology of the tissue. The tissue cells lose their ability to divide, especially in articular cartilage where the chondrocytes are poorly nourished. PGs produced from aging chondrocytes are very different from those produced by younger cells and alters the hydrostatic properties of the joint.

Species, site, zone and region of connective tissue dictate changes, both qualitative and quantitative, in PGs. However, age has the most notable effect on composition and stability of the extracellular matrix. PGs in the matrix have a protective effect on the collagen network. Continued loss of PGs and other matrix components appear to activate loss of collagen from connective tissues. For instance, a reduction of the size of hyaluronan and reduced stability of the GAG chains are age related. Studies (1,4) validate that concentration of small PG monomers increases with age. The resulting decrease in load absorption and redistribution properties is less efficient and renders the tissue more prone to damage.

Vogel et al showed that generally the alterations in the pattern of morphology and proteoglycan composition varied little in tendons with increasing age after puberty. However, PGs from tendons of younger individuals had greater homogeneity in GAG chain length. Effects of aging, however, may be tissue and site specific. For example, some ligaments maintain their mechanical characteristics throughout the life of the organism, whereas others show deterioration of strength with advanced age. Amount and composition of proteoglycans in human ligamentum flavum of the spine changed with age contributing to the ossification (calcification) of the tissue (3).

Osteoarthritis (OA) is the most common degenerative disease associated with aging of joint connective tissue. Degradation of the extracellular matrix is responsible for the pathogenesis of OA and is frequently associated with predisposing conditions such as traumatic injury to the joint. Chondrocytes in articular cartilage with OA may be unresponsive to local growth factors resulting in decreased synthesis of matrix components. Increased amounts of catabolic substances reduce concentrations of proteoglycans and glycoproteins resulting in reductions in tensile strength and resiliency.

Changes in connective tissue in diabetics parallel those evident in aging and cause many complications seen in later stage diabetes. The most apparent clinical disorders affect the skin, eyes, arteries and kidneys. Arteries and joints of diabetics become prematurely stiff with decreased elasticity. Nonenzymatic glycation of collagen protein and oxidative stress are associated with aging and diabetes, and caused by hyperglycemia (�glucose toxicity�) (4,5,6 ,7, 8). Excessive plasma and tissue glucose undergo reactions that produce advanced glycation products. The long-lived proteins of collagen and elastin accumulate enough advanced glycation products that irreversibly alter many of the protein�s physical properties. The collagen becomes saturated and excessively cross-linked inhibiting normal turnover. Progressive changes in properties ultimately modify arrangements and functioning of the tissue (8). These alterations in the matrix may affect cell behavior such as migration, growth, proliferation and gene expression.

Glycation is the nonenzymatic reaction between a sugar and the free amino acid group of proteins. Several mechanisms initiate glycation including glucose auto-oxidation and the Amadori degradation pathway. Lipid peroxidation (oxidation of polyunsaturated fatty acids) may also contribute to oxidative reactants. Intermediates of carbohydrate peroxidation are similar to lipid peroxidation; both form carboxymethyllysine (CML). Under oxidative conditions and in the presence of a transition metal, such as copper or iron, CML forms and accumulates in tissue, altering collagen cross-linking. Other advanced glycation products also affect the physical, chemical and mechanical properties of collagen protein. Collagen becomes browned and excessively cross-linked, altering its tensile strength. Diabetic rats exhibit acceleration of procollagen degradation in tendons (9). An interventional strategy that shows success in animal models is glycemic control and is discussed further along with carbohydrate nutrition.

Excessive or high-intensity exercise may be traumatic to the body�s skeletal system and result in acute or overuse injuries that are discussed previously. Low-intensity exercise is not considered to be injurious to a healthy normal individual. In fact, immobilization can impair normal metabolism and remodeling of connective tissue. When a joint is immobilized, the diminished mechanical loading and unloading of cartilage and surrounding tissues interferes with normal turnover of cells and matrix components. Decreased stimulation of cells results in decreased proteoglycan synthesis. Consequently, matrix loss leads to increased vulnerability of the tissue to injury when normal activities are resumed.

Studies in animal models have shown exercise to be beneficial to healthy metabolism of connective tissues. Brown et al (10) measured urine levels of hydroxyproline (HP), hydroxylysine (HL) and pyridinoline (PYD) as indirect markers of connective tissue breakdown and remodeling after a bout of eccentric exercise. These amino acid biomarkers characteristic to cross-linking are released during breakdown and remodeling of collagen and elastin. Post-exercise levels of urine HP, HL and PYD increased indicating that eccentric exercise may disrupt skeletal muscle and connective tissue structures. The delay (two days after exercise bout) in increased biomarker levels suggest that breakdown is not immediate and does not result directly from mechanical damage to connective tissue. Otherwise, urine biomarker levels should increase within 24 hours. The authors suggest that connective tissue breakdown results from the localized inflammatory response to exercise-induced musculo-tendon trauma. Inflammatory mediators from inflammation in the musculo-tendon unit may promote collagen breakdown and subsequent synthesis in surrounding connective tissues.

Exercise may contribute to long- and short-term stimulation of cartilage metabolism by mechanical loading of the joints. Compression of the joint capsule induced by mechanical loading changes joint fluid and pressure, osmotic pressure, cell-matrix interactions and cell activities. In animal models (11), post-exercise PG synthesis was enhanced and breakdown was reduced in the carpel joint synovial fluid. Cartilage degradation was impaired and the extracellular matrix was more stable. Several studies (10,11) suggest that the effects of mechanical loading on articular cartilage metabolism is mediated by changes in composition and humoral factors released into the synovial fluid.

As many athletes know, exercise may increase turnover of muscle and connective tissue by elevated breakdown and synthesis. Nutritional aspects of muscle tissue remodeling are routinely addressed in weightlifting and fitness periodicals. However, connective tissue receives little attention except for occasional mention in training techniques and programs. Supplement companies have recently begun to add nutritional supplements to their product lines for connective tissue. Unfortunately, weight lifters (and the general public) generally know less about physiology of connective tissue than muscle tissue and may be confused with supplement advertisement claims. Some of these products may indeed benefit connective tissue health and integrity. Nonetheless, they can not replace a proper diet. Let us take a look at the nutritional macronutrients and discuss how they influence connective tissue turnover and remodeling.

Nearly all knowledge gathered about the nutritional influences on human connective tissues is extrapolated from investigations with in vitro tissue/cell research, animal models, and clinical and surgical practice. Human in vivo investigations are costly and relatively difficult because serum levels of nutrients ordinarily inadequately reflect total body content. Measuring total body level of specific nutrients is complex and sometimes impossible. As well, measuring direct clinical effects on specific tissues resulting from individual nutrients in humans is equally complicated. Nearly all human measurements are indirect and from clinical studies.

Many studies demonstrate that collagen production is sensitive to changes in short and long-term food intake. Within 24 hours of fasting of some animal models, collagen synthesis in articular cartilage decreases to 50% of normal. This reduction declines to 8-12% of control levels after 96 hours. Most conditions are not as severe as starvation. However, energy restriction may reduce collagen synthesis depending on duration and degree of food deprivation. Specific effects of malnutrition on connective tissue turnover are dependant on many factors such as exercise activities, injuries, and disease. As well, nutrition restriction effects may be age-related. Youngsters that are still growing are more sensitive to nutritional changes. Replacement of tissue pools of macronutrients requires weeks to months and certainly affects turnover rates of tissue components. Likewise, dietary deficiencies or excess and physical activities influence turnover rates.

Calories provide the body with cellular energy for normal metabolism, building and repairing tissues and stimulate hormonal responses. Individuals with injuries or other trauma should avoid a decrease in calories below maintenance or slightly above, thereby providing the nutrients and energy needed for healing and repair. Considering that connective tissue structures are created from all macronutrients, each are discussed below.

Severe caloric restriction is usually accompanied by protein deficiency. The two major sources of protein during times of bulk loss are muscle and connective tissue. Muscle tissue provides a steady source amino acids (AAs) for general body needs. Connective tissue is the second source, which is reflective of the relative rate of turnover to muscle tissue. Many studies have demonstrated that a protein deficient diet results in a reduction of growth and development of the organism as well as delay in wound healing and repairs.

All of the essential AAs are required for synthesis of proteins and other components and growth factors in the extracellular matrix. Some studies show that supplementing certain individual AAs (methionine, lysine, arginine, and proline) to a protein deficient diet may inhibit prolongation of the inflammation phase of connective tissue healing and aid in fiber cross-linking mechanisms during repair.

Although countless studies demonstrate that protein malnutrition is significantly detrimental to normal turnover and healing of connective tissues, most athletes are generally well nourished with protein intake. Unless an individual is presented with severe trauma, surgery, or diabetes, a protein deficit that would negatively affect normal connective tissue metabolism should not be an issue.

For more general information on dietary protein and metabolism, read the series of articles by Lyle McDonald in past issues of Mesomorphosis.

Aside from protein, carbohydrates are a major component of an athlete�s diet and supply quick energy for the body in the form of glucose. Although little information exits on the direct effects of glucose deficiencies on connective tissues, it is well known that glucose is an energy source for several components and growth mediators. Phagocytes and other white cells that mediate the inflammatory process utilize glucose as an energy source. Activity by these cells during the acute and healing phases prepare tissue for repair after injury. Tissue cells such as fibroblasts and chondroblasts require glucose for synthesis of various macromolecules. Glucose is a building block of glycosaminoglycans and glycoproteins in the ground substance of the matrix. Arguably, hypoglycemia (abnormally low level of plasma glucose) impairs normal cell function and delays wound healing. As well, production and release of several hormones, such as insulin and growth hormone, decline with low levels of plasma glucose further delaying tissue growth and repair.

Conversely, high levels of plasma glucose may also be detrimental. Decreased insulin function may lead to hyperglycemia (abnormally high levels of plasma glucose) which also impairs wound healing. High levels of plasma glucose reportedly may inhibit the stimulatory action of ascorbic acid on proteoglycan and collagen production (15). Furthermore, recall that chronic high plasma and tissue glucose levels produce advanced glycation products that affect the physical, chemical and mechanical properties of collagen and elastin protein. Although associated with aging, this process is prematurely evident in diabetics. Proper glycemic control may delay the onset of complications related to excessive glycation and oxidation stress (6). For diabetics, exogenous insulin may be necessary for glycemic control. Additionally, avoiding a diet with excessive carbohydrate intake may postpone effects of high accumulation of glycation and oxidative products.

Diets low in carbohydrates typically cause body water loss. For athletes, the resultant dehydration may compromise integrity of connective tissues subject to mechanical loading. Considering that many connective tissues such as in articular joints require a relatively high water content for optimal functioning under stress, dehydration may increase incidence of injury or jeopardize healing and repair of injured tissue.

Fats are very calorically dense and provide energy for the body. Furthermore, saturated fats and polyunsaturated fatty acids (PUFAs) are precursors for many hormones such as steroids and prostaglandins. PUFAs are essential constituents of the cell membrane, contributing to their structural and functional integrity. Saturated fats are commonly found in animal foods and in some vegetable plants and have little direct import in the physiology of connective tissue. Therefore, discussion will concentrate on the influences of PUFAs and their influence on injured connective tissue.

The major PUFAs are classified as two types: n-3 and n-6 PUFAs. The n-6 family is the major PUFA in cell membranes and is derived from vegetable oils. Low levels of n-3 PUFAs exist in most individual cell membranes because diets are generally low in fish oils which are the source of this PUFA family. PUFAs are precursors for a family of hormones called eicosanoids, which are released by macrophages and other cells and mediate many cellular functions. These substances have powerful autocrine (act on cell where released) and paracrine (act on nearby cell) actions. The major role of eicosanoids is in the inflammatory response; therefore, dietary PUFAs may moderate the length of the inflammatory phase.

The n-6 PUFAs are precursors for arachidonic acid and the series 1 and 3 eicosanoids. Eicosapentanoic acid and eicosanoid series 2 are formed from the n-3 PUFAs. Generally, the 1 and 3 eicosanoid series are anti-inflammatory and the series 2 eicosanoids are pro-inflammatory. A relative excess of n-6 PUFAs stimulates production of prostaglandin E₂ which may prolong the inflammatory response.

Dietary n-3 PUFAs can replace n-6 PUFAs. Increasing the ratio of dietary n-3:n-6 PUFAs may decrease macrophage prostaglandin E₂ and cytokine release, and a balance between the eicosanoids may maintain the repair process with the least amount of inflammation. Although increasing intake of n-3 PUFAs may not impact acute inflammation, such nutritional support quite possibly moderate long-term inflammation related to excessive prostaglandin E₂ production and cytokine release from activated macrophages.

As we have seen, dietary macronutrient deficiencies and excesses influence metabolism of connective tissue components during growth, stress, and repair. As well, vitamins and minerals play significant roles in connective tissue metabolism and will be addressed in Part 3 of this series. Conceivably, nutrition may be used as adjunct therapy for tissue repair. However, most commonly, pharmaceuticals are used to moderate symptoms of inflammation resulting from injuries and may potentially interfere with normal turnover or repair of tissues. Some of these applications, including nutriceuticals, will be examined in Part 3 along with their effects on connective tissue physiology.

References

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Connective Tissue Part II: The Good, The Bad and the Ugly

References