Connective Tissues: Matrix Composition and Its Relevance to Physical Therapy.

Key Words: Connective tissues, Fibers, Function, Proteoglycans.

[Culav EM, Clark CH, Merrilees MJ. Connective tissues: matrix composition and its relevance to physical therapy. Phys Ther. 1999;79:308-319.]

The purposes of this update are to provide an overview of the composition, structure, and function of the connective tissue (CT) matrix and to illustrate how recent research has contributed to an improved understanding of the ways in which CT responds to mechanical forces. The overview is not exhaustive, but rather seeks to illustrate the complexity of these tissues, tissues once regarded as relatively simple structures within a mechanical system. Specific tissues and their special features, such as those of cartilage and bone, are not discussed in depth; instead, the overview emphasizes general principles that apply across the CT spectrum.

Components of Connective Tissues

Connective tissues and their matrix components make up a large proportion of the total body mass, are highly specialized, and have a diversity of roles. They provide for mechanical support, movement, tissue fluid transport, cell migration, wound healing, and--as is becoming increasingly evident--control of metabolic processes in other tissues.[1, 2] Unlike the properties of epithelial, muscle, or nerve tissues, which depend primarily on their cellular elements, the properties of CT are determined primarily by the amount, type, and arrangement of an abundant extracellular matrix (ECM). The ECM consists of g major types of macromolecules--fibers, proteoglycans (PGs), and glycoproteins--each of which is synthesized and maintained by cells specific to the tissue type (Fig. 1).

[Figure 1 ILLUSTRATION OMITTED]

The 2 most important fibrous components of the ECM are collagen and elastin, both insoluble macromolecular proteins. Collagen has a variety of forms but is perhaps best exemplified by the prominent aligned fibers of tendons and ligaments. Other collagen fibers, which are far less prominent, include the small reticular fibers of soft organs such as the liver and the submicroscopic fibrils found in basement membranes. The striking feature of the most prominent collagens is their ability to resist tensile loads. Generally, they show minimal elongation (less than 10%) under tension; a proportion of this elongation is not the result of true elongation of individual fibers, but of the straightening of fibers that are packed in various 3-dimensional arrays.[3,4] In contrast, elastic fibers may increase their length by 150%, yet still return to their previous configuration.[3]

The second major component of the ECM is the PGs, a diverse group of soluble macromolecules that have both structural and metabolic roles.[5,6] They occupy, along with collagen, the interstitial spaces between the cells, form part of basement membranes, and attach to cell surfaces where they function as receptors.[5,6] Important mechanical functions of PGs include hydration of the matrix, stabilization of collagen networks, and the ability to resist compressive forces, an ability best exhibited by the PGs of articular cartilage.[5] Hyaluronan (HA), which is technically not a PG because it lacks a protein core, is particularly important because it readily entrains large amounts of water and is abundant in hydrated soft loose tissues where repeated movement is required (eg, tendon sheaths and bursae).[7,8]

The third group of matrix molecules, the glycoproteins, are ubiquitous in all CTs and, as with the PGs, have both structural and metabolic roles. Their mechanical roles include providing linkage between matrix components and between cells and matrix components.

An important concept is that the mechanical properties of CT, such as the ability to resist tension, compression, extensibility, and torsion, are determined by the proportions of the matrix components. In turn, the maintenance of these matrix components and their organization depend on the nature and extent of loading these tissues experience. Generally, tissues with a high collagen-fiber content and low amounts of PG resist tensile forces, and those tissues with a high PG content, combined with a network of collagen fibers, withstand compression (Tab. 1). Trauma or pathology may affect normal movements and lead to changed mechanical stresses placed on the CT.

Table 1. Major Extracellular Matrix Components and Mechanical Properties of the Common Connective Tissues1(1,7,a)

                 Principal Cell    Dominant
Tissue           Type              Fiber

Tendon           Tenocytes         Collagen

Articular        Chondrocytes      Collagen
  cartilage

Bone             Osteoblasts       Collagen
                 Osteocytes

Dermis           Fibroblasts       Collagen
                                   Elastin

                 Dominant PG/GAG and Total GAG
Tissue           Content

Tendon           Dermatan sulphate PG ~0.2% of dry
                   weight

Articular        Chondroitin sulphate PG ~8%-10% of
  cartilage        dry weight

Bone             Chondroitin sulphate PG
                 Very small percentage of dry weight

Dermis           Dermatan and chondroitin sulphate PG
                   ~1% of dry weight

Tissue           Mechanical Properties

Tendon           Resists tensional forces

Articular        Resists compressive forces
  cartilage

Bone             Resists tension, compression, and
                   torsion (due to hydroxyapatite)

Dermis           Resists tension and moderate
                   compression and accomodates
                   stretching

PG = proteoglycan, GAG = glycosaininoglycan.

This, in turn, produces changes in the ECM and at the level of gene expression, as will be discussed below.

Collagens: Framework of the Extracellular Matrix

Nineteen distinct types of collagens are recognized, all with individual characteristics that serve specific functions in a variety of tissues.[9] The common structural feature that identifies all collagens, however, is a triple helix region within the molecule. This section of the molecule provides the characteristic mechanical properties of tendons and ligaments (ie, the ability to withstand tensile loads).

The triple helix is made up of 3 polypeptide chains folded to form a ropelike coil. Each chain, known as an [Alpha]-chain, is characterized by repeating sequences of 3 amino acids, glycine-X-Y (Fig. 2). Because glycine is the smallest amino acid and occupies the central core of the triple helix, the repetition of glycine as every third amino acid is essential for the correct folding of the 3 [Alpha]-chains into the helical conformation,[10,11] Specific collagen types are formed by a variety of [Alpha]-chains and by variations in the combination of different [Alpha]-chains: in some collagens, all 3 [Alpha]-chains are identical; in other collagens, 2 a-chains may be identical; and in some collagens, all 3 a-chains are different. Alteration of the glycine-X-Y sequence of amino acids usually results in dysfunction of the collagen molecule and loss of its mechanical properties (eg, osteogenesis imperfecta).[12] The helical complex, which inherently resists tension, is further strengthened by intermolecular bonds between the a-chains of adjacent molecules.[13]

[Figure 2 ILLUSTRATION OMITTED]

The extremities or terminals of the collagen molecule are nonhelical but are important for the formation of collagen fibrils and for other nontensile functions, including interactions with other extracellular components. The [Alpha]-chains of me principal collagens are synthesized with relatively long extremities, and, after formation of the triple helix, this newly formed collagen molecule (called procollagen) is emitted from the cell into the extracellular space where most of the nonhelical ends are enzymatically removed. Removal allows the shortened molecules, now called tropocollagen, to associate with each other and form fibrils, which are visible under the electron microscope and characterized by distinct cross-bands. These fibrils then aggregate to form fibers, which are visible under the light microscope, and bundles of fibers, which are visible to the eye[14] (Fig. 3).

[Figure 3 ILLUSTRATION OMITTED]

Modifications, variations, and additions to the basic triple-helix conformation give rise to 6 classes of collagens (Tab. 2).[9,10] Of most relevance to physical therapists are the fibril-forming collagens that are found in tissues (ie, tendons, ligaments) where their primary function is to resist tensile forces and in tissues where there is a requirement for resisting tensile loads (ie, dermis, articular cartilage, intervertebral disks [IVDs], bone). The other 5 classes of collagen, which are much less abundant but nevertheless essential to CT functions throughout the body, have a variety of roles.[9,10] These classes of collagen and their roles are summarized in Table 2.

Table 2.
Collagen Types, Location, and Functions[9,10]

Classes of Collagen                    Collagen Types

Fibril-forming collagens               I, II, III, V, XI

Fibril-associated collagens with       IX, XII, XIV, XVI
  interrupted triple helices (FACIT)

Network-forming collagens              IV

Filamentous collagens

Short-chain collagens                  VIII, X, XIII

Long-chain collagens                   VII

Classes of Collagen                    Examples of Location

Fibril-forming collagens               Tendon, ligament,
                                         intervertebral disk, bone,
                                         cartilage, blood vessels,
                                         dermis

Fibril-associated collagens with       Coassemble with fibril-
  interrupted triple helices (FACIT)     forming collagens (eg,
                                         type IX  and type II) in
                                         cartilage

Network-forming collagens              Basement membranes

Filamentous collagens                  Ubiquitous in connective
                                         tissue

Short-chain collagens                  VIII: cornea and vascular
                                         tissue
                                       X: hyaline cartilage
                                       XIII: blood vessel wall,
                                         glomeruli of kidney

Long-chain collagens                   Basement membrane

Classes of Collagen                    Functions

Fibril-forming collagens               I, II, III: resist tension
                                       V, XI: control fibril
                                         diameter

Fibril-associated collagens with       Interact with other matrix
  interrupted triple helices (FACIT)     components

Network-forming collagens              Separates tissue
                                         compartments
                                       Surrounds many cell types
                                       (eg, smooth muscle cells and
                                         nerve cells)
                                       Plays a role in regulation
                                         of cell growth, migration,
                                         and differentiation

Filamentous collagens                  Bridges and anchors cells to
                                         other components of
                                         extracellular matrix
                                       Important in development and
                                         maintenance of tissues

Short-chain collagens                  Unknown

Long-chain collagens                   Secures basement membrane to
                                       adjacent connective tissue
                                         matrix

Fibril-forming collagens (types I, II, III, V, and XI). Fibril-forming collagens account for over 70% of the total collagen found in the body.[10] Type I collagen predominates in tissues such as bones, tendons, ligaments, joint capsules, and the annulus fibrosus of the IVD. Type II collagen is located principally in articular cartilage and the nucleus pulposus of the IVD. Type III collagen appears to play a role in the extensibility of tissue and is found especially in embryonic tissues and in many adult tissues, such as arteries, skin, and soft organs, where they form reticular fibers.[11,15] The prevalence of type III collagen is also an indicator of tissue maturity and is also prominent in the initial stages of healing and scar-tissue formation, where it provides early mechanical strength to the newly synthesized matrix.[14] As fetal development proceeds and as healing tissue gains in strength, type III fibers are replaced by the stronger type I fibers.[16-18] Generally, type I fibrils have a large diameter, a feature that correlates with the ability to carry a greater mechanical load. In young, growing tendons, exercise increases fibril diameter and ultimate tensile strength, but, in the adult, the effect of exercise is minimal. Nevertheless, continued tension is necessary to maintain tendon structure because immobilization leads to a loss of tensile strength.[19]

Fibrils may also be formed of more than one type of collagen. Types V and XI combine with type I and II collagen, respectively, to form heterotypic fibrils, an arrangement that is thought to play a role in determining fibril diameter and thereby influence mechanical properties. In general, the greater the fibril diameter, the smaller the percentage of type V and type XI collagen.[11]

The tension-resisting property of the fibril-forming collagens is the principal means of limiting the range of motion of joints, transmitting forces generated by muscle, imparting tensile strength to the bony skeleton, and resisting extension by the surface layers of articular cartilage. The arrangement and alignment of the collagen fibers reflect the mechanical stresses acting on the tissues.

In tendons, the majority of fibers are aligned in parallel, enabling them to resist unidirectional forces and to efficiently transmit forces generated by muscles to bones.[4] In comparison, type I fibers in ligaments are often positioned in slightly less parallel arrays, reflecting the need to resist multidirectional forces. For example, in ligaments associated with joints, there is a need to both limit motion and provide for joint stability. Collagen also plays an important role in attaching tendons and ligaments to bone. At these junctions, tendons and ligaments usually widen and give way to fibrocartilage, a transformation where the aligned fibers originating from the tendon or ligament are separated by other collagen fibers arranged in a 3-dimensional network surrounding rounded cells.[20] This arrangement helps to transmit tensile forces onto a broad area and reduces the chance of failure under excessive loading.

The type I collagen fibers of bone have a more complex arrangement. Generally, the fibrils are arranged in orthogonal arrays, similar to the way the wood fibers in plywood are arranged in alternating sheets. This arrangement, especially when configured as small cylinders, such as in osteons, imparts a great deal of multidirectional tensile strength.

A combination of type I and type II collagen is found in the IVD and in tendons with fibrocartilaginous pressure pads.[21] In the annulus fibrosus of the IVD, alternating layers of type I fibers link adjacent vertebral bodies and surround the central nucleus pulposus. The fibrous bands are generally aligned at angles of about 45 degrees from the vertebral axis, an arrangement that provides a mechanism for spinal flexibility and for increasing resistance to excessive motion near the limits of movement. In the nucleus pulposus, type II collagen predominates and there are high levels of HA and sulphated PG that function in association with the type II fibers to provide a hydrated and pressure-resistant core.[22]

In articular cartilage, the principal collagen fibers are type II, which are arranged to form a network of bands between the cells. Superficially, these fibrous bands are mostly tangential to the articular surface, but, with increasing depth, they become more radial and pass between columns of cells. Immediately around the cells, other type II collagen fibers combine with types VI, IX, and XI in a dense capsule arrangement. These fibrous bands provide both the tensile properties of cartilage and, in conjunction with large sulphated PG, a mechanism for resisting compression. The capsular collagen is thought to protect the chondrocytes from these external Forces.[23,24]

Elastic fibers: extensible elements of the extracellular matrix. Elastic fibers in the ECM allow tissues such as skin, the lungs, and blood vessels to withstand repeated stretching and considerable deformation and to return to a relaxed state. The arrangement of elastin varies and depends largely on the strength and direction of forces on the tissue. The fibers may be organized into concentric fenestrated sheets (eg, aorta), as small individual fibers (eg, skin, lung), or as a 3-dimensional honeycomb-like network of fine fibers (eg, elastic cartilage).[25]

Elastic fibers are composed of an elastin core and microfibrils located mostly around the periphery (Fig. 4). The microfibrils, which are chiefly made up of fibrillin, initially act as a scaffold on which elastin is deposited, but once the core elastin is generated, the majority of microfibrils are displaced to the outer aspect of the fiber. Elastin contains 2 amino acids (ie, desmosine and isodesmosine) that form cross-linkages between adjacent tropoelastin chains and are important in imparting the elastic properties to elastin.[26] The exact mechanism of extensibility is not clearly understood, but the quantity of elastin found within the tissue usually reflects the amount of mechanical strain imposed on it and the requirement for reversible deformation (for a review of elastin see Chadwick and Goode[27]).

[Figure 4 ILLUSTRATION OMITTED]

Elastic fibers are widely distributed and found in most organs to varying degrees. They are found throughout the tracheobronchial tree of the lung and are largely responsible for accommodating pressure changes.[28] The potential energy stored in the elastic fiber at the end of inspiration is released during expiration with the consequent assisted recoil of the lung tissue.[28] Similarly, the elastin that is found in the walls of arteries withstands the deformation produced by systole, recoils during diastole, and accommodates the hemodynamic stresses that the flow of blood imposes on the artery wall.[25,29]

In the dermis, the elastic fibers provide the characteristic resilience of skin. There is a preferential orientation with coiled fibers aligning predominantly at right angles to lines of skin tension and in a direction that allows for greater stretching of the skin.[18] Both a changed conformation and general loss of elastic fibers with increasing age reduce the ability of the skin to recoil.[30]

Elastic fibers are relatively sparse in ligaments, with 2 notable exceptions: the ligamenta nuchae in the cervical region of the vertebral column and the ligamenta flava connecting the laminae of adjacent vertebrae?.[31] The elastic recoil in these ligaments assists in extending the head, neck, and trunk against gravity, thereby reducing the load imposed on the erector spinae muscles of the back. The lack of regeneration of functional elastic fibers in adults is a major problem, and, once this ability to regenerate is lost, the restoration of normal function is not possible.[30] Elastin, however, is synthesized by adult tissues in response to cyclic stretching, injury, and ultraviolet radiation[32] and by tissues in a number of disease states, including emphysema.[33] Adults, however, apparently cannot rebuild the elastic fiber assembly mechanisms, and function is not restored.[27] In general, there is a lack of knowledge about the mechanisms of control of elastic fiber formation.[27]

Proteoglycans: Hydrators, Stabilizers, and Space Fillers of the Extracellular Matrix

The PCs are characterized by a core protein covalently attached to one or more sulphated glycosaminoglycan (GAG) side chains. The core proteins are generally specific to each of the PG types and show considerable variability in size. Similarly, there are various GAG chains. The GAG chains are composed of repeating disaccharide units, with the type and number of units largely determining the properties of the PG.[5] Combinations of sugars make up the disaccharide units, resulting in 6 major GAGs: chondroitin sulphates 4 (CS A) and 6 (CS C), keratan sulphate (KS), dermatan sulphate (DS, also known as CS B), heparan sulphate, and HA. Hyaluronan is atypical because it is not attached to a protein core, nor is it sulphated. It is usually included under a discussion of PC, however, because it is the most abundant and ubiquitous of the GAGs, and it plays an important role in bonding to other PCs to form supramolecular complexes.

All GAGs are negatively charged and have a propensity to attract ions, creating an osmotic imbalance that results in the PC-GAG absorbing water from surrounding areas. This absorption helps maintain the hydration of the matrix; the degree of hydration depends on the number of GAG chains and on the restriction placed on PG swelling by the surrounding collagen fibers.[6]

The percentage of GAG within CT varies directly with mechanical load. Tissues subjected to high compressive forces (eg, articular cartilage) have a large PG content (approximately 8%-10% of the dry weight of the tissue). Conversely, in tension-resisting tissues such as tendons and ligaments, PGs are found in relatively small concentrations (approximately 0.2% of dry weight).[7] Furthermore, the proportions of PG species differ with the mechanical load in such a way that the CS:DS ratio is higher in tissues subjected to compression and lower in tissues that resist tension.[7]

Proteoglycan can be divided into aggregating and nonaggregating PGs. The key features that distinguish between these 2 groups are their ability or inability to aggregate with HA and the number of GAG side chains that bond to the protein core.[7]

Aggregating proteoglycans. Aggregating PGs bond to HA. A large complex results when many PG monomers link to a single strand of HA. The PG-HA linkage is stabilized by a glycoprotein known as link protein that helps secure the PG monomers to the HA.[34] Because the GAG chains attached to the PG core are negatively charged and extend from the core protein like the bristles of a bottle brush, a high charge density is created. This charge density induces an osmotic swelling pressure, resulting in the movement of water into the matrix. Therefore, the PG will tend to swell, but the tension-resistant collagen fibers and the bonding of the negatively charged GAG chains to regions of positive charge on collagen fibrils limits the expansion of PGs to approximately 20% of their swelling capacity.[35,36] This limited expansion provides the rigidity of the matrix and, where PG content is high, endows the tissue with the ability to resist compressive forces. Two examples of aggregating PGs are aggrecan and versican.

Aggrecan is the best-known and best-understood aggregating PG. It is the predominant PG in articular cartilage and plays a major role in normal joint function and in skeletal growth.[6,37] A large compliment of CS chains (approximately 100) and a smaller compliment of KS chains (approximately 30) are attached to the protein core of the monomer (Fig. 5). Versican has fewer CS chains (approximately 30) attached to its core protein, but it also aggregates with HA and contributes to resistance of compressive forces.[5] Versican is found in many tissues, including blood vessel walls,[36] the IVD,[22] and some tendon sites that are subjected to compressive loading.[21] Versican, along with HA, also functions as an antiadhesive molecule and facilitates cell migration.[38,39]

[Figure 5 ILLUSTRATION OMITTED]

Nonaggregating proteoglycans. The nonaggregating PGs do not bond to HA and frequently possess only a small number of GAG side chains composed of CS and DS. They appear to play a limited role in withstanding compression, but they interact with other matrix components and contribute to mechanical stability through interaction with collagen. Decorin, which has one GAG chain, is one of the smallest PGs and functions, in part, to link adjacent collagen fibrils. The core proteins bind at specific sites on the surface of fibrils, and the GAG chain extends to form an antiparallel array with a neighboring decorin GAG chain extending from an adjacent fibril.[40] Biglycan (2 GAG chains) is also small and is found in the matrix between bundles of collagen fibrils. The mechanical and other functions of biglycan are not understood, but both biglycan and decorin play a role in regulating cell activity, most notably through the binding of growth factors through specific high- and low-affinity sites on the core proteins[41] (Fig. 6).

[Figure 6 ILLUSTRATION OMITTED]

The heparan sulphate PG, syndecan, is attached to the cell membrane and plays a role in cell growth through binding growth factors, such as basic fibroblast growth factor, and acting as a co-receptor.[42,43] Perlecan is found close to cell surfaces and contributes to the structure of basement membranes. In addition to providing support, it assists in cellular differentiation.[44]

Hyaluronan is an important component of the aggrecan complex, but it also exists as a free molecule. Hyaluronan avidly entrains water and is prominent where the matrix is highly hydrated, such as in loose CT.[7,8] A relatively rich solution of HA is found in the vitreous humor of the eye, the umbilical cord, and the synovial fluid of joints where its theological properties are suited for lubrication.[45,46]

Role of mechanical forces in determining proteoglycan content and type. There is good evidence to show that the maintanence of normal tissue architecture requires normal physiological mechanical loading and that CTs respond to changes in applied stresses by altering their PG content and type.

Joint motion is important for the normal maintenance and turnover of PG in healthy articular cartilage. Conversely, joint immobilization or disuse results in atrophy of the articular cartilage because of a loss of PG from the matrix.[37] Importantly, this PG loss following joint immobilization is reversible with a remobilization program.[37,47]

Movement alone, without weight bearing, is sufficient to maintain PG content in sheep articular cartilage.[48] The absence of both weight bearing and movement, however, resulted in a large loss (40%) of PG over a period of 1 month.

Arthritic diseases induced by trauma or degenerative processes also lead to a disturbance in aggrecan synthesis and degradation and in the inability of the aggrecan monomer to bond to HA and form large aggregates.[49] As a result, cartilage may fail to resist compression effectively.

The load-bearing IVD also has a high PG content, with the PG being concentrated mostly in the nucleus pulposus and decreasing peripherally toward the annulus fibrosus, where the tissue is under increasing tension. Even the outer region of the annulus fibrosus, however, has a higher PG content than major tension-resisting structures such as tendons and ligaments, reflecting the need to resist both tension and pressure. Failure of the IVD may result, in part, from the inability of the aggrecan and HA to form a stable complex because of the fragmentation of the link protein.[50]

In flexor tendons that are angulated around a bony prominence, the outer portion of the tendon subjected to tension has a low PG content, with a high proportion of dermatan sulphate PG.[7] In contrast, the deeper part of the tendon that is compressed against the bony surface has a high PG content, with a high proportion of chondroitin sulphate PG.[7,51] Cell morphology also changes.[51] In the region under tension, the cells are greatly elongated. In the pressure region, they are rounded and similar to fibrocartilage cells. Importantly, the removal of the compressive forces by translocation of the tendon results in rapid (within 2 weeks) remodeling and loss of chondroitin sulphate PG from the pressure-bearing region. With the application of tension, total PG content decreases, but with a rise in the proportion of dermatan sulphate PG. The return of the tendon to its original position results in a slow (months) increase in PG content.[7]

More recently, it has been shown that lateral compression of fetal tendons leads to marked changes in specific PGs and at the level of the gene.[52] Aggrecan and biglycan messenger ribonucleic acids (mRNAs) were increased without a change in decorin or type I collagen mRNAs. Furthermore, these changes appeared to be driven by increased synthesis of a specific growth factor (ie, transforming growth factor beta) that is known to be a potent stimulator for aggrecan and biglycan synthesis but not decorin.[52]

Glycoproteins: Stabilizers and Linkers of the Extracellular Matrix

Glycoproteins constitute a small, but important, proportion of the total matrix components. They are soluble, multidomain, multifunctional macromolecules. Although they do not have prominent mechanical functions, they are integral to stabilizing the surrounding matrix and linking the matrix to the cell.[53] They are credited with the regulation of many functions, including producing changes in cell shape, enhancing cell motility, and stimulating cell proliferation and differentiation.[53] Among the best-characterized glycoproteins are fibronectin, tenascin, laminin, link protein, thrombospondin, osteopontin, and fibromodulin. Fibronectin is widespread in the ECM of most CTs and plays a role in cell attachment to matrix components through, for example, integrin receptors; tenascin, also involved in modulating cell attachment, is widespread in embryonic tissues and in certain adult tissues including the myotendinous junction; and laminin contributes to basement membrane structure.[53-57] Link protein, as discussed above, is required to stabilize the PG aggregates in the cartilage matrix, fibromodulin interacts with various matrix components and controls collagen fibril formation, osteopontin sequesters calcium and promotes tissue calcification, and thrombospondin plays a role in cell attachment.[34,53]

Changes to the Matrix in Connective Tissue Diseases and Injury

Under normal physiological conditions, the maintenance of fibers, PG, and glycoproteins is tightly regulated and controlled through a balance between synthesis and degradation. This balance is maintained largely by stimulatory cytokines and growth factors in addition to the degradative matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs).[58] The synthesis and secretion of MMPs and TIMPs is similarly modulated by an intricate network of signaling factors, cytokines, growth factors, and hormones.[58]

The alteration of the balance between synthesis and degradation influences normal tissue architecture, impairs organ function, and changes the mechanical properties of the tissues. As a general observation, net degradation of matrix components occurs in osteoarthritis, rheumatoid arthritis, pulmonary emphysema, and osteoporosis. Net increases in synthesis over degradation leads to accumulation of ECM in fibrotic conditions, such as interstitial pulmonary fibrosis, liver fibrosis, and the sclerodermas.

Trauma to CT also alters function. A partial or complete rupture of CT through excessive tensile loading commonly occurs in ligaments and tendons and at musculo-tendinous junctions. As a general principle, the loss of tensile loading, or compressive loading in the case of articular cartilage in a joint,[48] leads to rapid tissue deterioration.[59] The repair and remodeling of these structures is usually slow, taking many months, but follows a generally predicable pattern.[26,59] During the initial stages of healing, rupture sites are bridged by newly synthesized type III collagen, but, as remodeling proceeds, increasing amounts of type I collagen predominate and provide greater strength.[20]

Physical exercise also appears to have a beneficial effect on the strength of normal tendons and ligaments, although the results are somewhat equivocal. This may be because normal tendons and ligaments are in an optimal state.[60]

Tension exerted on wounds is also thought to stimulate collagen synthesis and enhance the repair process by causing the collagen fibrils to align parallel to the direction of force sooner than for wounds that are not subjected to tension.[18] The degree of tension exerted on healing skin wounds, however, is more problematic, as prolonged tension leads to hypertrophic scarring where excess sulphated PGs produce a thickened dermis.[61,62]

Summary

In the last 2 decades, the understanding of CT structure and function has increased enormously. It is now clear that the cells of the various GTs synthesize a variety of ECM components that act not only to underpin the specific biomechanical and functional properties of tissues, but also to regulate a variety of cellular functions. Importantly for the physical therapist, and as discussed above, CTs are responsive to changes in the mechanical environment, both naturally occurring and applied.

The relative proportions of collagens and PGs largely determine the mechanical properties of CTs. The relationship between the fibril-forming collagens and PG concentration is reciprocal. Connective tissues designed to resist high tensile forces are high in collagen and low in total PG content (mostly dermatan sulphate PGs), whereas CTs subjected to compressive forces have a greater PG content (mostly chondroitin sulphate PGs). Hyaluronan has multiple roles and not only provides tissue hydration and facilitatation of gliding and sliding movements but also forms an integral component of large PG aggregates in pressure-resisting tissues. The smaller glycoproteins help to stabilize and link collagens and PGs to the cell surface. The result is a complex interacting network of matrix molecules[5,10,53] (Fig. 7), which determines both the mechanical properties and the metabolic responses of tissues.

[Figure 7 ILLUSTRATION OMITTED]

Patients with CT problems affecting movement are frequently examined and treated by physical therapists. A knowledge of the CT matrix composition and its relationship to the biomechanical properties of these tissues, particularly the predictable responses to changing mechanical forces, offers an opportunity to provide a rational basis for treatments. The complexity of the interplay among the components, however, requires that further research be undertaken to determine more precisely the effects of treatments on the structure and function of CTs.

Acknowledgment

We thank Mr Arthur Ellis, Department of Anatomy With Radiology, School of Medicine, The University of Auckland, for assistance with preparation of the figures.

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EM Culav, MHSc(Hons), BPT, is Senior Lecturer, School of Physiotherapy, Faculty of Health Studies, Auckland Institute of Technology, Private Bag 92006, Auckland 1020, New Zealand ([e-mail]). Address all correspondence to Ms Culav.

CH Clark, MHSc(Hons), BSc, Dip Phys, is Senior Lecturer, School of Physiotherapy, Faculty of Health Studies, Auckland Institute of Technology.

MJ Merrilees, PhD, is Associate Professor, Department of Anatomy With Radiology, School of Medicine, The University of Auckland, Auckland, New Zealand.