Tendons are dynamic structures; their extracellular matrices are continuously being synthesised and broken down over the course of an individual’s lifetime. The macromolecules, namely collagen, proteoglycans, hyaluronan and the non-collagenous proteins form the extracellular matrix of tendons. In normal tendon exists a fine balance between the synthesis and degradation of these macromolecules resulting in a strong healthy tendon. It is evident that damage to tendons, such as in overuse tendinopathy results in changes to the levels and types of macromolecules present in tendon with decreased levels of collagen and increased levels of proteoglycans, hyaluronan and non-collagenous proteins, causing a weakened tendon that is prone to rupture.
These degenerative features have thus far been partially characterised. By identifying the levels and various types of macromolecules present in normal tendons and tendons exhibiting overuse tendinopathy an understanding of the basis of the condition can be determined and possible ways of preventing or ameliorating tendon degeneration can be considered. The terms overuse tendinopathy and pathological tendon will be used interchangeably throughout this study.
This literature review will attempt to define and characterise the structural and functional properties of tendon and will discuss the current literature regarding the levels, types, synthesis and catabolism of macromolecules present in the extracellular matrix of tendons and also attempt to define and characterise the pathological aspects of overuse tendinopathies. Chapter Two of this thesis will dictate the materials and methodology used in these studies. Chapters Three, Four and Five will present the results of this thesis. Finally, chapter Six will include the discussion and discuss any limitations and future considerations.
1.1 Synovial Joint
Joints are articulations found between adjacent parts of bone that allow controlled frictionless movement (for review see; Mankin & Radin, 1997). In the human body there are three different types of joints and these are grouped according to the type of movement they make. They include the freely movable joints (synovial joints; i.e., most joints of the extremities such as the knee joint), slightly movable (cartilaginous joints; i.e., the vertebrae and ribs) and those that are immovable (fibrous joints; i.e., the skull). The majority of the joints found in the human body are synovial joints (for review see; Mankin & Radin, 1997).
There are six different types of synovial joints including the ball-and-socket joints, hinge joints, saddle joint, pivot joint, gliding joints and condyloid joints. A synovial joint contains a joint cavity that is enclosed by a fibrous capsule linking the adjoining bones. This joint capsule is lined by a synovial membrane that secretes a lubricating and nutritious fluid called synovial fluid that is rich in albumin and hyaluronan. The surface of each bone is typically covered with articular hyaline cartilage or in some circumstances fibrocartilage. In addition, the joint capsule is supported by accessory structures such as tendons and ligaments, which provide stability to the synovial joint (Sledge et al., 2001).
1.1.1 Articular Cartilage
Articular cartilage covers the adjoining ends of bones in joints and has a white colour (for review see; Mankin & Radin, 1997). It is a tissue that is devoid of blood and nerves and provides a wear resistant surface with low frictional properties for the joint and attains its nutrients via diffusion from the synovium into the synovial fluid (for review see; Mankin & Radin, 1997). Furthermore, articular cartilage is resilient and flexible. This allows articular cartilage to withstand large compressive and tensile forces as well as allowing it to distribute load on subchondral bone during joint loading (Kempson, 1980) even though it is only a few millimetres thick (Hardingham, 1998).
Its biomechanical properties are dependent on the structural composition of the extracellular matrix, which is comprised of water (70-80%), collagens (predominantly Type II collagen), proteoglycans (predominantly aggrecan) and non-collagenous proteins (Kuettner et al., 1991; Poole, 1997). The predominant cell type present in articular cartilage is called the chondrocyte. These cells are responsible for the maintenance, synthesis and degradation of all the extracellular matrix components (Kuettner et al., 1991; Buckwalter & Mankin, 1998).
Mature articular cartilage can be divided up into four zones including the superficial (tangential) zone, the middle (transitional) zone, the deep (radial) zone and the zone of calcified cartilage (Huber et al., 2000). The organisation and composition as well as mechanical properties of the extracellular matrix varies within these zones. The deeper zones have high proteoglycan levels and low cellularity whereas the more superficial zones contain low proteoglycan levels and increased cellularity (Aydelotte et al., 1988; Buckwalter & Mankin, 1998).
1.1.2 Joint Capsule and Ligament
The joint capsule is a fibrous connective tissue that is attached to the skeletal parts of a joint beyond their articular surfaces. The principal function of the joint capsule is to seal the joint space and to supply stability by limiting movement (for review see; Mankin & Radin, 1997). Most joint capsules are strengthened by ligaments. Ligaments act together with the joint capsule and the peri-articular muscles to provide stability to the joint preventing excessive movements. They permit free movements when lax, but can stop unwanted movements when tight by virtue of their high tensile strength.
Occasionally joint capsules are strengthened by tendons, such as the extensor tendon in the finger joint. The joint capsule and ligaments proceed to hold the bones together and to guide and limit joint movements. Ligaments attach one bone with another bone and have a limited vascular and neural supply which enable them to repair relatively well after damage (Bray et al., 1990). The knee joint is a good example of different types of ligaments. The medial collateral ligament fuses with the joint capsule, and the cruciate ligaments and the lateral collateral ligament, which are both completely independent of the joint capsule.
1.1.3 Synovial Membrane
The synovial membrane (synovium) lines the non-articular surfaces of a joint such as the joint capsule and ligaments, and is responsible for secreting and absorbing synovial fluid, which contains hyaluronan (Mason et al., 1999). Synovial fluid lubricates the joint and provides at least partly for the nutrition of articular cartilage, invertebral discs and menisci. The synovial extracellular matrix acts as a scaffolding to support synoviocytes and plays an important role in cell migration and differentiation. It is mostly composed of collagen particularly Type III collagen, with smaller amounts of proteoglycans such as decorin and biglycan (Mason et al., 1999), non-collagenous proteins such as fibronectin, elastin and lamina, hyaluronic acid as well as lipids, serum proteins and electrolytes (Hirohata & Kobayashi, 1964).
The synovial membrane has only been detected in vertebrate animals (Henderson & Edwards, 1987). Furthermore, synovial tissue is not arranged into discrete layers, but rather represents a continuum from surface to deep zones. The extracellular matrix of the synovial membrane varies in composition from its surface to its deep zones (Hirohata & Kobayashi, 1964).
Tendons are dense fibrous connective tissues found between muscles and bones (for review see; Benjamin & Ralphs, 1997). The primary role of tendon is to absorb and transmit force generated by muscle to the bone to provide movement at a joint. In addition tendons operate as a buffer by absorbing forces to limit muscle damage. Each individual muscle has two tendons, one that is proximal and the other distal. The attachment of the proximal tendon of a muscle to bone is called a muscle origin and that of the distal tendon an insertion.
A normal tendon has a bright white colour and a fibroelastic texture and enables resistance to mechanical forces. Tendons come in many shapes and this is most likely due to their function, they can be round or oval in cross section or they can come in the form of flattened sheets, fan shaped, ribbon shaped or cylindrical in shape (for review see; Benjamin & Ralphs, 1997). In a muscle like the quadriceps which creates strong forces the tendons are short and broad, while those that are involved in more delicate movements like the finger flexors, long and thin tendons are present (Kannus, 2000).
Tendons are arranged in a hierarchical fashion (see Figure 1.1). A group of collagen fibres form a primary fibre bundle or subfascicle; this is the basic unit of tendon. A group of subfascicles form secondary bundles or fascicles, which form tertiary bundles constituting the tendon as a whole. The primary, secondary and tertiary bundles are encased in a thin connective tissue reticulum called the endotenon (Elliott, 1965; Kastelic et al., 1978; Rowe, 1985). The endotenon carries blood vessels, nerves and lymphatics to deeper areas of the tendon (Elliott, 1965; Hess et al., 1989). The whole tendon is surrounded by an epitenon, which is a dense fibrillar network of collagen (Jozsa et al., 1991).
The epitenon is contiguous with the endotenon and like the endotenon is rich in blood vessels, nerves and lymphatics (Hess et al., 1989). Many tendons are surrounded by a connective tissue called the paratenon. Paratenon allows free movement of the tendon against the surrounding tissues (Schatzker & Branemark, 1969; Hess et al., 1989). The myotendinous junction is the site of union with a muscle, and the osteotendinous junction is the site of union with a bone (Kannus, 2000).
In tendon, blood vessels represent between 1-2% of the entire extracellular matrix (Lang, 1960; Lang, 1963). Some blood vessels may originate from the perimysium at the musculotendinous junction and blood vessels from the osteotendinous junction (Schatzker & Branemark, 1969; Carr & Norris, 1989; Clark et al., 2000). At rest, rabbit tendons have been shown to have blood flow of around one-third that of muscle, and it is known that blood flow in tendon increases with exercise and during healing in animals (Backman et al., 1991). The oxygen consumption of tendons is 7.5 times lower than that of skeletal muscles (Vailas et al., 1978).
1.1.5 Tendon Extracellular Matrix
The major cell type present in tendon is the fibroblast (also known as tenocytes; Ross et al., 1989; Schweitzer et al., 2001; Salingcarnboriboon et al., 2003), which are embedded within an extracellular matrix (see Figure 1.2). These cells are sparsely distributed, comprising only 5% of the dry weight of adult tendon (Ross et al., 1989; Schweitzer et al., 2001; Salingcarnboriboon et al., 2003). These cells lie in longitudinal rows and have many cell extensions that extend into the extracellular matrix (McNeilly et al., 1996). Fibroblasts are responsible for the synthesis and degradation of all the macromolecular components that make up the extracellular matrix of tendon, including the most abundant macromolecule present in tendon, collagen, as well as proteoglycans, hyaluronan and non-collagenous proteins (Vogel & Heinegard, 1985; Curwin, 1997; O’Brien, 1997).
The extracellular matrix is made up of parallel bundles of collagen aligned longitudinally (60-85% of tendon dry weight) associated with elastin fibres which constitutes approximately 1-2% of the dry weight of tendon (Tipton et al., 1975; Hess et al., 1989; Jozsa et al., 1989; Curwin, 1997; Kirkendall & Garrett, 1997; O’Brien, 1997). Tendon consists of 55-70% water, most of which is associated with proteoglycans in the extracellular matrix (Elliott, 1965; Vogel, 1977; Merrilees & Flint, 1980; Riley et al., 1994b; Vogel & Meyers, 1999). The proteoglycan content of tendons is approximately 1% of dry weight of tendons (O’Brien, 1997).Water and proteoglycans have important lubricating and spacing roles in tendons that allow collagen fibres to glide over one another (Amiel et al., 1984).
The structure, composition and the organisation of the tendon matrix is crucial for the physical properties that tendons posses (Riley, 2004). The collagen component gives tendon its great tensile strength (Scott, 2003) whereas it is the proteoglycan component of the tendon matrix that enables tendons to withstand compressive load (Schonherr et al., 1995), while elastin fibres increase tendon extensibility (Scott, 2003).
1.1.6 Tendon cells
The cell population of tendon has so far been poorly characterised (for review see; Riley, 2000), the majority of tendon cells have the appearance of fibroblasts (also known as tenocytes) and constitute about 90-95% of the cells present in tendon (Ross et al., 1989; Schweitzer et al., 2001; Salingcarnboriboon et al., 2003). The remaining 5% to 10% of cells present in tendon are chondrocyte-like cells (fibrochondrocytes), which are mostly present in the fibrocartilaginous regions of tendon where tendon attaches to bone. Also present in tendon are some mast cells, capillary endothelial cells, smooth muscle cells and nerve cells (Hess et al., 1989; Jozsa & Kannus, 1997).
Fibrocartilage cells are large and have an oval shape and they are often packed with intermediate filaments (Merrilees & Flint, 1980; Ralphs et al., 1991). Tendon cells are linked to one another via gap junctions (McNeilly et al., 1996; Ralphs et al., 1998), allowing cell-to-cell interactions (McNeilly et al., 1996). Fibroblasts have a branched cytoplasm surrounding an elliptical, speckled nucleus. The rough endoplasmic reticulum and the Golgi apparatus are well developed with few mitochondria in the cytoplasm (Ippolito et al., 1980; Moore & De Beaux, 1987). Like other connective tissue cells, fibroblasts are derived from mesenchyme.
It is believed that in tendon there are a small number of mesenchymal stem cells that have the ability to differentiate into chondrogenic, osteogenic and adipogenic cells if the conditions allow (Salingcarnboriboon et al., 2003). Tendons have been shown to respond to mechanical load by modifying their extracellular matrix (Banes et al., 1988; Ehlers & Vogel, 1998; Buchanan & Marsh, 2002; Lavagnino & Arnoczky, 2005). Tendon cells receive their vascular supply from the surrounding paratenon.
Tendons were once considered almost static and unable to participate in repair. However, the activity of tendon cells has been shown to be active throughout an individual’s life as they express various matrix components (Chard et al., 1987; Ireland et al., 2001; Riley et al., 2002). Regional differences in cell morphology and activity exists in tendons, synovial-like cells that are found in the endotenon and epitenon surround the main fibre bundles (Banes et al., 1988). A greater proliferative capacity and a different matrix synthetic activity is characteristic of these synovial-like cells compared to the fibroblasts within the fibres, and are the first cells to respond following acute tendon injury (Gelberman et al., 1986; Banes et al., 1988; Garner et al., 1989; Gelberman et al., 1991; Khan et al., 1996b).
Tendon Extracellular Matrix Macromolecules
The following section will discuss the major extracellular matrix proteins and their roles in tendon. This will include the major constituent of tendon, collagen, the small and large proteoglycans and the non-collagenous proteins as well as hyaluronan. This section will also discuss the synthesis of collagens, proteoglycans and hyaluronan.
Collagen is the most copious protein present in the extracellular matrix of connective tissues and accounts for approximately 90% of the total protein of tendons, or 65% to 75% of the dry weight of tendons (von der Mark, 1981; O’Brien, 1992). There are currently 28 different collagen types (numbered I-XXVIII) present in vertebrates with at least 42 different alpha chains (Veit et al., 2006) with this number continuing to mount (Brown & Timpl, 1995; Aumailley & Gayraud, 1998). Collagen molecules can be defined as an extracellular protein that contains at least one triple helical domain (van der Rest & Bruckner, 1993). Collagen provides the tendon with its structural integrity as well as assisting in various physiological functions.
Collagen consists of three polypeptide alpha chains, which combine to form a homotrimer (three identical alpha chains) or a heterotrimer (two or three different alpha chains). Covalent bonds known as collagen cross-links develop between individual collagen molecules in a collagen fibre (Eyre et al., 1984; Bailey et al., 1998; Bailey, 2001; Brady & Robins, 2001). The collagen arrangement gives tendon its great tensile strength. Cross-links are formed from a pathway of different chemical reactions that result in divalent cross-links that join two polypeptide chains, to multivalent, i.e. tri- or even tetravalent, cross-links (Bailey & Lapiere, 1973; Eyre et al., 1984). These cross-links come about from enzymatic modification of lysine or hydroxylysine residues by the copper-dependent enzyme lysine oxidase (Robins, 1988).
Collagens are divided into two subgroups, the fibrillar and non-fibrillar collagens. Non-fibrillar collagens can be further divided into seven subfamilies including microfibril collagens, fibril-associated collagens with interrupted helices (FACIT) collagens, network collagens, MULTIPLEXIN collagens (proteins with multiple triple helix domains and interruptions), basement membrane-associated collagens, transmembrane-associated collagens and epithelium-associated collagens (von der Mark, 1999). The non-fibrillar collagens present in tendon include Types IV, VI, IX, X, XII and XIV (von der Mark, 1999).
The fibrillar collagens present in tendon include, Types I, II, III, V and XI (Kielty et al., 1993; Kadler et al., 1996; Fukuta et al., 1998; von der Mark, 1999). The fibrillar collagens contain a continuous triple helix domain, 300 nm in length, capable of undergoing the staggered, lateral associations required to form fibrils (Mayne, 1997). The resulting fibrils provide the structural support for tissues. All the fibril-forming collagens have a similar structure and size, being composed of a large, continuous central triple-helical domain (COL1) of approximately 1000 amino-acid residues
Occurs in most tissues, tendon, bone, skin etc
Main component of tendon, skin, bone, dentin, cartilage, ligament etc
Hyaline cartilage, invertebral disc
Restricted to fibrocartilage; forms less-organised meshwork
Vessels, kidney, liver, skin, tendon
Normally restricted to endotenon; forms smaller less organised fibrils
Basement membranes, tendon
Basement membrane of tendon blood vessels
Core of Type I collagen fibril – forms template for fibrillogenesis
Vessels, skin, intervertebral disc
Cell associated – found in seams between fibrils
Forms anchoring fibrils in the skin
Descements membrane in the cornea
Forms a lattice
Hyaline cartilage, vitreous humour, tendon
Cell and matrix interactions with Type II collagen fibril surface
Growth plate, tendon
Restricted to insertion fibrocartilage
Core of Type II collagen fibril – forms template for fibrillogenesis
Embryonic tendon and skin, periodontal ligament
Mediates cell/matrix interactions with Type I collagen fibril surface
Adhesion of cells to basement membranes
Foetal skin, tendon
Mediates cell/matrix interactions with Type I collagen fibril surface
Stabilizes skeletal muscle cells and microvessels
Skin, cornea, lung
Connects epithelial cells to the matrix
Endothelial cells, liver, eye
Needed for normal development of the eye
Forms radially distributed aggregates
Corneal epithelium, skin, cartilage and tendon
Binds to collagen fibrils
Matrix assembly of vascular networks in blood vessel formation
Interacts with components of microfibrils
Metastatic tumour cells, heart retina
Cell adhesion, Binds to heparin
Expressed in tissues containing Type I collagen Developing bone and cornea
Regulating Type I collagen fibrillogenesis
May play a role in adherens junctions between neurons
Testis and ovary of adult tissues
Development of the reproductive tissues
Cartilage, ear, eye and lung
Basement membranes around Schwann cells in the peripheral nervous system.
flanked by a variable amino-terminal domain of about 50-520 amino acid residues and a highly conserved non-triple-helical carboxyl-terminal domain of about 250 amino acid residues (for reviews see; Kielty et al., 1993; Fichard et al., 1995; Pihlajaniemi & Rehn, 1995; Prockop & Kivirikko, 1995; Bateman et al., 1996). The amino- and carboxyl-terminal extensions are commonly referred to as amino- and carboxyl- propeptides, respectively. The C-propeptide is called the NC1 domain, whereas the amino-propeptide is divided into sub-domains. The first is a short sequence (NC2) that links the major triple helix to the minor one (COL2) and a globular amino-terminal end (NC3) that shows structural and splicing variations.
Collagen Types II, IX, X and XI (Fukuta et al., 1998) are present at specific sites within the fibrocartilage region of tendon, found at the bone insertion and where the tendon is subjected to shear forces or compression (Fukuta et al., 1998; Waggett et al., 1998). Collagen Types II, IX, X and XI were once thought to occur only in cartilage (Visconti et al., 1996; Fukuta et al., 1998; Riley, 2000). It has now been shown that these collagens are found in the fibrocartilaginous regions of tendon, which wraps under bone. Their presumed function is to help resist compression and shear forces at these sites (Visconti et al., 1996; Fukuta et al., 1998; Waggett et al., 1998).
Collagen also plays an important role in attaching tendons to bone. Where the tendon attaches to bone, tendons commonly widen and give way to fibrocartilage, a transformation where the aligned fibres originating from the tendon are separated by other collagen fibres arranged in a three dimensional network surrounding rounded cells (Liu et al., 1995). This arrangement helps to transmit tensile forces onto a broad area and reduces the chance of failure under excessive loading. The following review will focus on the collagens that are known to exist in tendon; this includes collagen Types I-VI, IX-XII and XIV.
18.104.22.168 Type I Collagen
Type I collagen is the predominant and most studied collagen type present in the extracellular matrix of tendon, ligament and bone representing approximately 95% of the total collagen content or 60% of the tendon dry weight (Evans & Barbenel, 1975; von der Mark, 1981; Riley et al., 1994b; Rufai et al., 1995). It is synthesized by a number of cell types such as fibroblasts, osteocytes and odontoblasts. Type I collagen consists of two α1(I) chains and a shorter α2(I) chain (Kielty et al., 1993), these two chains are products of separate genes and are not a posttranslational modification of a single molecule (for review see; Kivirikko & Prockop, 1995).
The two α1(I) and one α2(I) chains of a monomer of Type I collagen are primarily comprised of approximately 338 repeating tripeptide sequences of Gly-X-Y in which X is frequently proline and Y is frequently hydroxyproline (OHPr). The ends of the α1(I) and one α2(I) chains consist of short telopeptides of between 11-26 amino acids per chain.
In longitudinal sections, the monomers are arranged in fibrils in a head-to-head-to-tail orientation. Each Type I collagen molecule consists of a long central helical region with a short non-helical domain on both the amino- and carboxyl-terminal ends. In tendon, the Type I collagen-containing fibril, organized into fibres (fibril bundles), is the major element responsible for structure stabilization and the mechanical attributes of this tissue. The fibril contains collagen molecules assembled into a quarter-staggered array, and this striated fibril has a 67 nm periodicity (for review see; Kadler et al., 1996; Orgel et al., 2006).
Each alpha chain consists of a repeating triplet of glycine and two other amino acids marked as (Gly-X-Y)n. It is the glycine residues located in every third position that makes it possible for the three alpha chains to coil around the other. It has a molecular weight of 290 kDa. When viewing collagen fibrils under the light microscope they have a crimped appearance, during tendon loading the crimp stretches and the fibrils become aligned, and after loading the crimp will reappear, this is an important elastic component that tendon possesses (O’Brien, 1992).
The Type I collagen α chains contain approximately 290 residues of OHPr per molecule. Proline and OHPr constitute 20% to 25% of all amino acid residues of Type I collagen. The parallel arranged bundles formed by the Type I collagen fibrils gives tissues a high tensile strength with limited elasticity, and therefore is suitable for force transmission. The Type I collagen molecule has the ability to form microfibrils (filaments) as well as larger units of the fibrils or fibres (for review see; Kivirikko & Prockop, 1995). The diameter of the collagen fibril is usually between 20 nm and 150 nm but can range up to 300 nm, this depends on the stage of development (Dyer & Enna, 1976; Jozsa et al., 1984; Fleischmajer et al., 1988).
22.214.171.124 Type II Collagen
The homotrimeric Type II collagen molecule was first discovered in cartilage by Miller and Matukas in 1969 who extracted collagen from cartilage in an experiment that involved pepsin digestion. Type II collagen, although most commonly found in articular and hyaline cartilage is also expressed in tendon particularly around the fibrocartilaginous region and consists of three identical α1(II) chains (Eyre et al., 1992) which forms a meshwork structure that gives Type II collagen the ability to entrap the negatively charged proteoglycan molecules, thereby resisting the swelling pressure of proteoglycans. Each Type II collagen chain has a molecular weight of approximately 95 kDa.
The entire collagen Type II molecule is shaped like a thin rod and is 300 nm long and 1.5 nm wide and has a total combined molecular weight of 295 kDa. This molecule is essential in connective tissues that are subjected to compression such as tendon and articular cartilage. Type II collagen molecules consists of a long central helical region flanked at its amino- and carboxyl-terminus by short non-helical regions termed amino and carboxyl telopeptides (Eyre et al., 1992). As with all fibrillar collagens, Type II collagen molecules are arranged in a quarter-staggered array to form collagen fibrils. Lateral associations of these collagen fibrils forms collagen fibres (Mayne, 1997). In tendon, collagen Types IX and XI as well as the proteoglycans decorin, fibromodulin and lumican inhibit collagen Type II fibril formation reducing fibril thickness (Vogel et al., 1984; Hedbom & Heinegard, 1989; Hedbom & Heinegard, 1993).
126.96.36.199 Type III Collagen
Type III collagen is the second most abundant collagen present in tendon, representing up to 10% of the total collagen content in various tendons (Hanson & Bentley, 1983; Riley et al., 1994b). Type III collagen is a thin collagen fibre consisting of three α1(III) chains with a molecular weight of 290 kDa. In tendon most Type III collagen is found in the endotenon and epitenon (Duance et al., 1977), and is also found in between Type I collagen fibril bundles in aging tendons and at the insertion (Kumagai et al., 1994). It can also be found in skin, blood vessels, ligament and internal organs such as the gastro-intestinal tract but is not found in bone (Epstein & Munderloh, 1978; McCullagh et al., 1980; Amiel et al., 1984). It strengthens the walls of hollow structures like the intestines and uterus.
The fibrils of Type III collagen have a generally thinner diameter compared with Type I collagen fibrils (Lapiere et al., 1977; for review see; Kadler et al., 1996), however the triple helical domain is longer in length being composed of 340 amino acid repeats compared to 338 amino acid repeats in Type I collagen. In the early repair of the injured tendon, Type III collagen fibrils are quickly synthesized to restore strength and elasticity (Williams et al., 1984; Dahlgren et al., 2005). However, the fibrils do not have the same tensile strength quality as Type I collagen and so lack the functional properties needed in a tendon experiencing maximal load. The repair processes continues with Type III fibrils slowly being replaced by Type I collagen fibrils in an attempt to normalize the properties of the tendon (Duance et al., 1977; Williams et al., 1984; Dahlgren et al., 2005).
Type III collagen contains high levels of OHPr and glycine. It has been reported that these high levels of glycine may cause localised helix instability resulting in increased susceptibility to proteolytic cleavage and rapid turnover of the extracellular matrices containing this collagen (Linsenmayer, 1991). The frequency of Type III collagen is considered to be an indicator of tissue age, and is common in the early stages of healing and scar tissue formation where it provides mechanical strength to the matrix (Burgeson & Nimni, 1992).
188.8.131.52 Type IV Collagen
The non-fibrillar collagen, Type IV (Bailey et al., 1979), is a basement membrane-associated collagen (Light & Champion, 1984) composed of triple helical isoforms consisting of six genetically distinct chains [α1(IV) to α6(IV)]. Each chain is characterised by a long collagenous domain of approximately 1400 amino acid residues of Gly-X-Y repeats, that are interrupted at several sites by a short non-collagenous sequence and approximately 15 amino acid residue non-collagenous amino-terminus, and an approximately 230 amino acid residue non-collagenous domain at the carboxyl-terminus (Mayne, 1997). Type IV collagen has been reported to represent approximately 2% of the total collagen content of tendon (Ahtikoski et al., 2003). Unlike the fibrillar collagens discussed so far this collagen does not form fibrillar aggregates but are directly incorporated into the basement membrane without any prior excision of the pro-peptide extensions.
Type IV collagen is found uniquely in the basement membrane of tendon blood vessels (von der Mark, 1981) where it forms a key structural compo
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