Connective Tissues: Matrix Composition and Its …...Connective Tissues: Matrix Composition and Its...

Connective Tissues: MatrixComposition and Its Relevance toPhysical Therapy

The purposes of this update are to provide an overview of thecomposition, structure, and function of the connective tissue (CT)matrix and to illustrate how recent research has contributed to animproved understanding of the ways in which CT responds to

mechanical forces. The overview is not exhaustive, but rather seeks toillustrate the complexity of these tissues, tissues once regarded as relativelysimple structures within a mechanical system. Specific tissues and their specialfeatures, such as those of cartilage and bone, are not discussed in depth;instead, the overview emphasizes general principles that apply across the CTspectrum.

Components of Connective TissuesConnective tissues and their matrix components make up a large proportionof the total body mass, are highly specialized, and have a diversity of roles.They provide for mechanical support, movement, tissue fluid transport, cellmigration, wound healing, and—as is becoming increasingly evident—con-trol of metabolic processes in other tissues.1,2 Unlike the properties ofepithelial, muscle, or nerve tissues, which depend primarily on their cellularelements, the properties of CT are determined primarily by the amount, type,and arrangement of an abundant extracellular matrix (ECM). The ECMconsists of 3 major types of macromolecules—fibers, proteoglycans (PGs), andglycoproteins—each of which is synthesized and maintained by cells specificto the tissue type (Fig. 1).

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

@Culav EM, Clark CH, Merrilees MJ. Connective tissues: matrix composition and its relevance tophysical therapy. Phys Ther. 1999;79:308–319.#

308 Physical Therapy . Volume 79 . Number 3 . March 1999

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Elizabeth M Culav

C Heather Clark

Mervyn J Merrilees

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The 2 most important fibrous components of the ECMare collagen and elastin, both insoluble macromolecularproteins. Collagen has a variety of forms but is perhapsbest exemplified by the prominent aligned fibers oftendons and ligaments. Other collagen fibers, which arefar less prominent, include the small reticular fibers ofsoft organs such as the liver and the submicroscopicfibrils found in basement membranes. The strikingfeature of the most prominent collagens is their ability toresist tensile loads. Generally, they show minimal elon-gation (less than 10%) under tension; a proportion ofthis elongation is not the result of true elongation ofindividual fibers, but of the straightening of fibers thatare packed in various 3-dimensional arrays.3,4 In con-trast, elastic fibers may increase their length by 150%, yetstill return to their previous configuration.3

The second major component of the ECM is the PGs, adiverse group of soluble macromolecules that have bothstructural and metabolic roles.5,6 They occupy, alongwith collagen, the interstitial spaces between the cells,form part of basement membranes, and attach to cellsurfaces where they function as receptors.5,6 Importantmechanical functions of PGs include hydration of thematrix, stabilization of collagen networks, and the abilityto resist compressive forces, an ability best exhibitedby the PGs of articular cartilage.5 Hyaluronan (HA),which is technically not a PG because it lacks a proteincore, is particularly important because it readily en-

trains large amounts ofwater and is abundantin hydrated soft loosetissues where repeatedmovement is required(eg, tendon sheathsand bursae).7,8

The third group ofmatrix molecules, theglycoproteins, are ubiq-uitous in all CTs and,

as with the PGs, have both structural and metabolic roles.Their mechanical roles include providing linkage betweenmatrix components and between cells and matrixcomponents.

An important concept is that the mechanical properties ofCT, such as the ability to resist tension, compression,extensibility, and torsion, are determined by the propor-tions of the matrix components. In turn, the maintenanceof these matrix components and their organizationdepend on the nature and extent of loading these tissuesexperience. Generally, tissues with a high collagen-fibercontent and low amounts of PG resist tensile forces, andthose tissues with a high PG content, combined with anetwork of collagen fibers, withstand compression (Tab.1). Trauma or pathology may affect normal movementsand lead to changed mechanical stresses placed on the CT.

EM Culav, MHSc(Hons), BPT, is Senior Lecturer, School of Physiotherapy, Faculty of Health Studies, Auckland Institute of Technology, PrivateBag 92006, Auckland 1020, New Zealand ([email protected]). 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.

© 1999 by the American Physical Therapy Association Inc.

Connective tissuesand their matrixcomponents have adiversity of roles inproviding formechanical support,movement, tissuefluid transport, cellmigration, woundhealing, and—asis becomingincreasinglyevident—control ofmetabolic processes.

Physical Therapy . Volume 79 . Number 3 . March 1999 Culav et al . 309

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

Collagens: Framework of the Extracellular MatrixNineteen distinct types of collagens are recognized, allwith individual characteristics that serve specific func-tions in a variety of tissues.9 The common structuralfeature that identifies all collagens, however, is a triplehelix region within the molecule. This section of themolecule provides the characteristic mechanical proper-ties of tendons and ligaments (ie, the ability to withstandtensile loads).

The triple helix is made up of 3 polypeptide chains foldedto form a ropelike coil. Each chain, known as an a-chain, ischaracterized by repeating sequences of 3 amino acids,glycine-X-Y (Fig. 2). Because glycine is the smallest aminoacid and occupies the central core of the triple helix, therepetition of glycine as every third amino acid is essentialfor the correct folding of the 3 a-chains into the helicalconformation.10,11 Specific collagen types are formed by avariety of a-chains and by variations in the combination ofdifferent a-chains: in some collagens, all 3 a-chains are

identical; in other collagens, 2 a-chainsmay be identical; and in some collagens, all3 a-chains are different. Alteration of theglycine-X-Y sequence of amino acids usu-ally results in dysfunction of the collagenmolecule and loss of its mechanical prop-erties (eg, osteogenesis imperfecta).12 Thehelical complex, which inherently resiststension, is further strengthened by inter-molecular bonds between the a-chains ofadjacent molecules.13

The extremities or terminals of thecollagen molecule are nonhelical butare important for the formation of col-lagen fibrils and for other nontensilefunctions, including interactions with

other extracellular components. The a-chains of theprincipal collagens are synthesized with relatively longextremities, and, after formation of the triple helix, thisnewly formed collagen molecule (called procollagen) isemitted from the cell into the extracellular space wheremost of the nonhelical ends are enzymatically removed.Removal allows the shortened molecules, now calledtropocollagen, to associate with each other and formfibrils, which are visible under the electron microscopeand characterized by distinct cross-bands. These fibrilsthen aggregate to form fibers, which are visible underthe light microscope, and bundles of fibers, which arevisible to the eye14 (Fig. 3).

Modifications, variations, and additions to the basictriple-helix conformation give rise to 6 classes of collag-ens (Tab. 2).9,10 Of most relevance to physical therapistsare the fibril-forming collagens that are found in tissues(ie, tendons, ligaments) where their primary function isto resist tensile forces and in tissues where there is arequirement for resisting tensile loads (ie, dermis, artic-ular cartilage, intervertebral disks @IVDs#, bone). Theother 5 classes of collagen, which are much less abun-

Figure 1.Principal components of connective tissues.

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

TissuePrincipal CellType

DominantFiber

Dominant PG/GAG and Total GAGContent Mechanical Properties

Tendon Tenocytes Collagen Dermatan sulphate PG ;0.2% of dryweight

Resists tensional forces

Articularcartilage

Chondrocytes Collagen Chondroitin sulphate PG ;8%–10% ofdry weight

Resists compressive forces

Bone OsteoblastsOsteocytes

Collagen Chondroitin sulphate PGVery small percentage of dry weight

Resists tension, compression, andtorsion (due to hydroxyapatite)

Dermis Fibroblasts CollagenElastin

Dermatan and chondroitin sulphate PG;1% of dry weight

Resists tension and moderatecompression and accomodatesstretching

a PG5proteoglycan, GAG5glycosaminoglycan.

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dant but nevertheless essential to CT functions through-out the body, have a variety of roles.9,10 These classes ofcollagen and their roles are summarized in Table 2.

Fibril-forming collagens (types I, II, III, V, and XI). Fibril-forming collagens account for over 70% of the totalcollagen found in the body.10 Type I collagen predomi-nates in tissues such as bones, tendons, ligaments, jointcapsules, and the annulus fibrosus of the IVD. Type IIcollagen is located principally in articular cartilage andthe nucleus pulposus of the IVD. Type III collagenappears to play a role in the extensibility of tissue and isfound especially in embryonic tissues and in many adulttissues, such as arteries, skin, and soft organs, where theyform reticular fibers.11,15 The prevalence of type IIIcollagen is also an indicator of tissue maturity and is alsoprominent in the initial stages of healing and scar-tissueformation, where it provides early mechanical strengthto the newly synthesized matrix.14 As fetal developmentproceeds and as healing tissue gains in strength, type IIIfibers are replaced by the stronger type I fibers.16–18

Generally, type I fibrils have a large diameter, a featurethat correlates with the ability to carry a greater mechan-ical load. In young, growing tendons, exercise increasesfibril diameter and ultimate tensile strength, but, in theadult, the effect of exercise is minimal. Nevertheless,continued tension is necessary to maintain tendon struc-ture because immobilization leads to a loss of tensilestrength.19

Fibrils may also be formed of more than one type ofcollagen. Types V and XI combine with type I and IIcollagen, respectively, to form heterotypic fibrils, anarrangement that is thought to play a role in determin-ing fibril diameter and thereby influence mechanical

properties. In general, the greater the fibril diameter,the smaller the percentage of type V and type XIcollagen.11

The tension-resisting property of the fibril-forming col-lagens is the principal means of limiting the range ofmotion of joints, transmitting forces generated bymuscle, imparting tensile strength to the bony skeleton,and resisting extension by the surface layers of articularcartilage. The arrangement and alignment of the collagenfibers reflect the mechanical stresses acting on the tissues.

In tendons, the majority of fibers are aligned in parallel,enabling them to resist unidirectional forces andto efficiently transmit forces generated by muscles tobones.4 In comparison, type I fibers in ligaments areoften positioned in slightly less parallel arrays, reflectingthe need to resist multidirectional forces. For example,in ligaments associated with joints, there is a need toboth limit motion and provide for joint stability. Colla-gen also plays an important role in attaching tendonsand ligaments to bone. At these junctions, tendons andligaments usually widen and give way to fibrocartilage, atransformation where the aligned fibers originatingfrom the tendon or ligament are separated by othercollagen fibers arranged in a 3-dimensional networksurrounding rounded cells.20 This arrangement helps totransmit tensile forces onto a broad area and reduces thechance of failure under excessive loading.

The type I collagen fibers of bone have a more complexarrangement. Generally, the fibrils are arranged inorthogonal arrays, similar to the way the wood fibers inplywood are arranged in alternating sheets. Thisarrangement, especially when configured as small cylin-

Figure 2.Portion of a collagen molecule showing individual alpha chains coiled to form a triple helix. Within each chain, the amino acids are similarlyarranged in a helix, with glycine (G) facing the center of the triple helix. The other amino acids are represented by the dots.


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ders, such as in osteons, imparts a great deal of multidi-rectional tensile strength.

A combination of type I and type II collagen is found inthe IVD and in tendons with fibrocartilaginous pressurepads.21 In the annulus fibrosus of the IVD, alternatinglayers of type I fibers link adjacent vertebral bodies andsurround the central nucleus pulposus. The fibrousbands are generally aligned at angles of about 45 degreesfrom the vertebral axis, an arrangement that provides amechanism for spinal flexibility and for increasing resis-tance to excessive motion near the limits of movement.In the nucleus pulposus, type II collagen predominatesand there are high levels of HA and sulphated PG thatfunction in association with the type II fibers to providea hydrated and pressure-resistant core.22

In articular cartilage, the principal collagen fibers aretype II, which are arranged to form a network of bandsbetween the cells. Superficially, these fibrous bands are

mostly tangential to the articular sur-face, but, with increasing depth, theybecome more radial and pass betweencolumns of cells. Immediately aroundthe cells, other type II collagen fiberscombine with types VI, IX, and XI in adense capsule arrangement. Thesefibrous bands provide both the tensileproperties of cartilage and, in conjunc-tion with large sulphated PG, a mecha-nism for resisting compression. Thecapsular collagen is thought to protectthe chondrocytes from these externalforces.23,24

Elastic fibers: extensible elements of theextracellular matrix. Elastic fibers inthe ECM allow tissues such as skin, thelungs, and blood vessels to withstandrepeated stretching and considerabledeformation and to return to a relaxedstate. The arrangement of elastin variesand depends largely on the strengthand direction of forces on the tissue.The fibers may be organized into con-centric fenestrated sheets (eg, aorta),as small individual fibers (eg, skin,lung), or as a 3-dimensional honey-comb-like network of fine fibers (eg,elastic cartilage).25

Elastic fibers are composed of an elas-tin core and microfibrils located mostlyaround the periphery (Fig. 4). Themicrofibrils, which are chiefly made upof fibrillin, initially act as a scaffold onwhich elastin is deposited, but once the

core elastin is generated, the majority of microfibrils aredisplaced to the outer aspect of the fiber. Elastin con-tains 2 amino acids (ie, desmosine and isodesmosine)that form cross-linkages between adjacent tropoelastinchains and are important in imparting the elastic prop-erties to elastin.26 The exact mechanism of extensibilityis not clearly understood, but the quantity of elastinfound within the tissue usually reflects the amount ofmechanical strain imposed on it and the requirementfor reversible deformation (for a review of elastin seeChadwick and Goode27).

Elastic fibers are widely distributed and found in mostorgans to varying degrees. They are found throughoutthe tracheobronchial tree of the lung and are largelyresponsible for accommodating pressure changes.28 Thepotential energy stored in the elastic fiber at the end ofinspiration is released during expiration with the conse-quent assisted recoil of the lung tissue.28 Similarly, the

Figure 3.Representation of collagen synthesis, secretion, and assembly. Adapted with permission fromKielty CM, Hopkinson I, Grant ME. Collagen: the collagen family, structure, assembly, andorganization in the extracellular matrix. In: Royce PM, Steinmann BS, eds. Connective Tissueand Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York, NY:Wiley-Liss; 1993:113.


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elastin that is found in the walls of arteries withstands thedeformation produced by systole, recoils during diastole,and accommodates the hemodynamic stresses that theflow of blood imposes on the artery wall.25,29

In the dermis, the elastic fibers provide the characteristicresilience of skin. There is a preferential orientation withcoiled fibers aligning predominantly at right angles tolines of skin tension and in a direction that allows forgreater stretching of the skin.18 Both a changed confor-mation and general loss of elastic fibers with increasingage reduce the ability of the skin to recoil.30

Elastic fibers are relatively sparse in ligaments, with 2notable exceptions: the ligamenta nuchae in the cervicalregion of the vertebral column and the ligamenta flavaconnecting the laminae of adjacent vertebrae.31 Theelastic recoil in these ligaments assists in extending thehead, neck, and trunk against gravity, thereby reducingthe load imposed on the erector spinae muscles of theback. The lack of regeneration of functional elasticfibers in adults is a major problem, and, once this abilityto regenerate is lost, the restoration of normal functionis not possible.30 Elastin, however, is synthesized by adulttissues in response to cyclic stretching, injury, and ultra-violet radiation32 and by tissues in a number of diseasestates, including emphysema.33 Adults, however, appar-ently cannot rebuild the elastic fiber assembly mecha-nisms, and function is not restored.27 In general, there is

a lack of knowledge about the mechanisms of control ofelastic fiber formation.27

Proteoglycans: Hydrators, Stabilizers, and Space Fillersof the Extracellular MatrixThe PGs are characterized by a core protein covalentlyattached to one or more sulphated glycosaminoglycan(GAG) side chains. The core proteins are generallyspecific to each of the PG types and show considerablevariability in size. Similarly, there are various GAGchains. The GAG chains are composed of repeatingdisaccharide units, with the type and number of unitslargely determining the properties of the PG.5 Combi-nations of sugars make up the disaccharide units, result-ing 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 aprotein core, nor is it sulphated. It is usually includedunder a discussion of PG, however, because it is the mostabundant and ubiquitous of the GAGs, and it plays animportant role in bonding to other PGs to formsupramolecular complexes.

All GAGs are negatively charged and have a propensityto attract ions, creating an osmotic imbalance thatresults in the PG-GAG absorbing water from surround-ing areas. This absorption helps maintain the hydrationof the matrix; the degree of hydration depends on the

Table 2.Collagen Types, Location, and Functions9,10

Classes of Collagen Collagen Types Examples of Location Functions

Fibril-forming collagens I, II, III, V, XI Tendon, ligament, intervertebral disk,bone, cartilage, blood vessels,dermis

I, II, III: resist tensionV, XI: control fibril diameter

Fibril-associated collagens withinterrupted triple helices (FACIT)

IX, XII, XIV, XVI Coassemble with fibril-formingcollagens (eg, type IX and type II)in cartilage

Interact with other matrixcomponents

Network-forming collagens IV Basement membranes Separates tissue compartmentsSurrounds many cell types(eg, smooth muscle cells and

nerve cells)Plays a role in regulation of cell

growth, migration, anddifferentiation

Filamentous collagens VI Ubiquitous in connective tissue Bridges and anchors cells to othercomponents of extracellularmatrix

Important in development andmaintenance of tissues

Short-chain collagens VIII, X, XIII VIII: cornea and vascular tissueX: hyaline cartilageXIII: blood vessel wall, glomeruli

of kidney

Unknown

Long-chain collagens VII Basement membrane Secures basement membrane toadjacent connective tissue matrix


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number of GAG chains and on the restriction placed onPG swelling by the surrounding collagen fibers.6

The percentage of GAG within CT varies directly withmechanical load. Tissues subjected to high compressiveforces (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 tendonsand ligaments, PGs are found in relatively small concen-trations (approximately 0.2% of dry weight).7 Further-more, the proportions of PG species differ with themechanical load in such a way that the CS:DS ratio ishigher in tissues subjected to compression and lower intissues that resist tension.7

Proteoglycan can be divided into aggregating and non-aggregating PGs. The key features that distinguishbetween these 2 groups are their ability or inability toaggregate with HA and the number of GAG side chainsthat bond to the protein core.5

Aggregating proteoglycans. Aggregating PGs bond toHA. A large complex results when many PG monomerslink to a single strand of HA. The PG-HA linkage isstabilized by a glycoprotein known as link protein thathelps secure the PG monomers to the HA.34 Because theGAG chains attached to the PG core are negativelycharged and extend from the core protein like thebristles of a bottle brush, a high charge density is

created. This charge density induces an osmotic swellingpressure, resulting in the movement of water into thematrix. Therefore, the PG will tend to swell, butthe tension-resistant collagen fibers and the bonding ofthe negatively charged GAG chains to regions of positivecharge on collagen fibrils limits the expansion of PGs toapproximately 20% of their swelling capacity.35,36 Thislimited expansion provides the rigidity of the matrixand, where PG content is high, endows the tissue withthe ability to resist compressive forces. Two examples ofaggregating PGs are aggrecan and versican.

Aggrecan is the best-known and best-understood aggre-gating PG. It is the predominant PG in articular cartilageand plays a major role in normal joint function and inskeletal growth.6,37 A large compliment of CS chains(approximately 100) and a smaller compliment of KSchains (approximately 30) are attached to the proteincore of the monomer (Fig. 5). Versican has fewer CSchains (approximately 30) attached to its core protein,but it also aggregates with HA and contributes to resis-tance of compressive forces.5 Versican is found in manytissues, including blood vessel walls,36 the IVD,22 andsome tendon sites that are subjected to compressiveloading.21 Versican, along with HA, also functions as anantiadhesive molecule and facilitates cell migration.38,39

Nonaggregating proteoglycans. The nonaggregatingPGs do not bond to HA and frequently possess only asmall number of GAG side chains composed of CS andDS. They appear to play a limited role in withstandingcompression, but they interact with other matrix com-ponents and contribute to mechanical stability throughinteraction with collagen. Decorin, which has one GAGchain, is one of the smallest PGs and functions, in part,to link adjacent collagen fibrils. The core proteins bindat specific sites on the surface of fibrils, and the GAGchain extends to form an antiparallel array with aneighboring decorin GAG chain extending from anadjacent fibril.40 Biglycan (2 GAG chains) is also smalland is found in the matrix between bundles of collagenfibrils. The mechanical and other functions of biglycanare not understood, but both biglycan and decorin playa role in regulating cell activity, most notably throughthe binding of growth factors through specific high- andlow-affinity sites on the core proteins41 (Fig. 6).

The heparan sulphate PG, syndecan, is attached to thecell membrane and plays a role in cell growth throughbinding growth factors, such as basic fibroblast growthfactor, and acting as a co-receptor.42,43 Perlecan is foundclose to cell surfaces and contributes to the structure ofbasement membranes. In addition to providing support,it assists in cellular differentiation.44

Figure 4.Representation of elastic fiber showing elastin core containing andsurrounded by microfibrils. Adapted with permission from Cormack DH.Essential Histology. Philadelphia, Pa: JB Lippincott Co; 1993:107.


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Hyaluronan is an important compo-nent of the aggrecan complex, but italso exists as a free molecule. Hyaluro-nan avidly entrains water and is prom-inent where the matrix is highlyhydrated, such as in loose CT.7,8 Arelatively rich solution of HA is foundin the vitreous humor of the eye, theumbilical cord, and the synovial fluid ofjoints where its rheological propertiesare suited for lubrication.45,46

Role of mechanical forces in determiningproteoglycan content and type. Thereis good evidence to show that the main-tanence of normal tissue architecturerequires normal physiological mechan-ical loading and that CTs respond tochanges in applied stresses by alteringtheir PG content and type.

Joint motion is important for the nor-mal maintenance and turnover of PGin healthy articular cartilage. Con-versely, joint immobilization or disuseresults in atrophy of the articular carti-lage because of a loss of PG from the matrix.37 Impor-tantly, this PG loss following joint immobilization is revers-ible with a remobilization program.37,47

Movement alone, without weight bearing, is sufficient tomaintain PG content in sheep articular cartilage.48 Theabsence of both weight bearing and movement, how-ever, resulted in a large loss (40%) of PG over a periodof 1 month.

Arthritic diseases induced by trauma or degenerativeprocesses also lead to a disturbance in aggrecan synthesisand degradation and in the inability of the aggrecanmonomer to bond to HA and form large aggregates.49

As a result, cartilage may fail to resist compressioneffectively.

The load-bearing IVD also has a high PG content, withthe PG being concentrated mostly in the nucleus pulpo-sus and decreasing peripherally toward the annulusfibrosus, where the tissue is under increasing tension.Even the outer region of the annulus fibrosus, however,has a higher PG content than major tension-resistingstructures such as tendons and ligaments, reflecting theneed to resist both tension and pressure. Failure of theIVD may result, in part, from the inability of the aggre-can and HA to form a stable complex because of thefragmentation of the link protein.50

In flexor tendons that are angulated around a bonyprominence, the outer portion of the tendon subjectedto tension has a low PG content, with a high proportionof dermatan sulphate PG.7 In contrast, the deeper partof the tendon that is compressed against the bonysurface has a high PG content, with a high proportion ofchondroitin sulphate PG.7,51 Cell morphology alsochanges.51 In the region under tension, the cells aregreatly elongated. In the pressure region, they arerounded and similar to fibrocartilage cells. Importantly,the removal of the compressive forces by translocation ofthe tendon results in rapid (within 2 weeks) remodelingand loss of chondroitin sulphate PG from the pressure-bearing region. With the application of tension, total PGcontent decreases, but with a rise in the proportion ofdermatan sulphate PG. The return of the tendon to itsoriginal position results in a slow (months) increase inPG content.7

More recently, it has been shown that lateral compres-sion of fetal tendons leads to marked changes in specificPGs and at the level of the gene.52 Aggrecan andbiglycan messenger ribonucleic acids (mRNAs) wereincreased without a change in decorin or type I collagenmRNAs. Furthermore, these changes appeared to bedriven by increased synthesis of a specific growth factor(ie, transforming growth factor beta) that is known to bea potent stimulator for aggrecan and biglycan synthesisbut not decorin.52

Figure 5.Representation of an aggrecan monomer with keratan sulphate (KS) and chondroitin sulphate(CS) glycosaminoglycan side chains attached to the protein core. The monomer is attached tohyaluronan and is stabilized at this binding region by link protein. Numerous monomers attachto hyaluronan to form the large proteoglycan aggregate. Adapted with permission fromHeinegard D, Oldberg A. Glycosylated matrix proteins. In: Royce PM, Steinmann B, eds.Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. NewYork, NY: Wiley-Liss; 1993:193.


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Glycoproteins: Stabilizers and Linkers of theExtracellular MatrixGlycoproteins constitute a small, but important, propor-tion of the total matrix components. They are soluble,multidomain, multifunctional macromolecules. Althoughthey do not have prominent mechanical functions, they areintegral to stabilizing the surrounding matrix and linkingthe matrix to the cell.53 They are credited with the regula-tion of many functions, including producing changesin cell shape, enhancing cell motility, and stimulatingcell proliferation and differentiation.53 Among the best-characterized glycoproteins are fibronectin, tenascin, lami-

nin, link protein, thrombospondin, osteopontin, and fibro-modulin. Fibronectin is widespread in the ECM of mostCTs and plays a role in cell attachment to matrixcomponents through, for example, integrin receptors;tenascin, also involved in modulating cell attachment, iswidespread in embryonic tissues and in certain adulttissues including the myotendinous junction; and lami-nin contributes to basement membrane structure.53–57

Link protein, as discussed above, is required to stabilizethe PG aggregates in the cartilage matrix, fibromodulininteracts with various matrix components and controlscollagen fibril formation, osteopontin sequesters cal-cium and promotes tissue calcification, and throm-bospondin plays a role in cell attachment.34,53

Changes to the Matrix in Connective TissueDiseases and InjuryUnder normal physiological conditions, the mainte-nance of fibers, PG, and glycoproteins is tightly regu-lated and controlled through a balance between synthe-sis and degradation. This balance is maintained largelyby stimulatory cytokines and growth factors in additionto the degradative matrix metalloproteinases (MMPs)and the tissue inhibitors of metalloproteinases(TIMPs).58 The synthesis and secretion of MMPs andTIMPs is similarly modulated by an intricate network ofsignaling factors, cytokines, growth factors, andhormones.58

The alteration of the balance between synthesis anddegradation influences normal tissue architecture,impairs organ function, and changes the mechanicalproperties of the tissues. As a general observation, netdegradation of matrix components occurs in osteoarthri-tis, rheumatoid arthritis, pulmonary emphysema, andosteoporosis. Net increases in synthesis over degradationleads to accumulation of ECM in fibrotic conditions,such as interstitial pulmonary fibrosis, liver fibrosis, andthe sclerodermas.

Trauma to CT also alters function. A partial or completerupture of CT through excessive tensile loading com-monly occurs in ligaments and tendons and at musculo-tendinous junctions. As a general principle, the loss oftensile loading, or compressive loading in the case ofarticular cartilage in a joint,48 leads to rapid tissuedeterioration.59 The repair and remodeling of thesestructures is usually slow, taking many months, butfollows a generally predicable pattern.26,59 During theinitial stages of healing, rupture sites are bridged bynewly synthesized type III collagen, but, as remodelingproceeds, increasing amounts of type I collagen predom-inate and provide greater strength.20

Physical exercise also appears to have a beneficial effecton the strength of normal tendons and ligaments,

Figure 6.Representation of biglycan (2 glycosaminoglycan side chains) and decorin(1 chain), with their similar core proteins. CS5chondroitin sulphate,DS5dermatan sulphate, S-S5disulphide bonds, Y5oligosaccharides.Adapted with permission from Heinegard D, Oldberg A. Glycosylatedmatrix proteins. In: Royce PM, Steinmann B, eds. Connective Tissue and ItsHeritable Disorders: Molecular, Genetic, and Medical Aspects. New York,NY: Wiley-Liss; 1993:198.


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although the results are somewhat equivocal. This maybe because normal tendons and ligaments are in anoptimal state.60

Tension exerted on wounds is also thought to stimulatecollagen synthesis and enhance the repair process bycausing the collagen fibrils to align parallel to thedirection of force sooner than for wounds that are notsubjected to tension.18 The degree of tension exerted onhealing skin wounds, however, is more problematic, asprolonged tension leads to hypertrophic scarring whereexcess sulphated PGs produce a thickened dermis.61,62

SummaryIn the last 2 decades, the understanding of CT structureand function has increased enormously. It is now clearthat the cells of the various CTs synthesize a variety ofECM components that act not only to underpin thespecific biomechanical and functional properties of tis-sues, but also to regulate a variety of cellular functions.Importantly for the physical therapist, and as discussedabove, CTs are responsive to changes in the mechanicalenvironment, both naturally occurring and applied.

The relative proportions of collagens and PGs largelydetermine the mechanical properties of CTs. The rela-tionship between the fibril-forming collagens and PGconcentration is reciprocal. Connective tissues designedto resist high tensile forces are high in collagen and lowin total PG content (mostly dermatan sulphate PGs),whereas CTs subjected to compressive forces have agreater PG content (mostly chondroitin sulphate PGs).Hyaluronan has multiple roles and not only providestissue hydration and facilitatation of gliding and sliding

movements but also forms an integral component oflarge PG aggregates in pressure-resisting tissues. Thesmaller glycoproteins help to stabilize and link collagensand PGs to the cell surface. The result is a complexinteracting network of matrix molecules5,10,53 (Fig. 7),which determines both the mechanical properties andthe metabolic responses of tissues.

Patients with CT problems affecting movement are fre-quently examined and treated by physical therapists. Aknowledge of the CT matrix composition and its rela-tionship to the biomechanical properties of these tissues,particularly the predictable responses to changingmechanical forces, offers an opportunity to provide arational basis for treatments. The complexity of theinterplay among the components, however, requires thatfurther research be undertaken to determine moreprecisely the effects of treatments on the structure andfunction of CTs.

AcknowledgmentWe thank Mr Arthur Ellis, Department of Anatomy WithRadiology, School of Medicine, The University of Auck-land, for assistance with preparation of the figures.

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Figure 7.Representation of typical components of the extracellular matrix and their interactions with each other and with receptors on the cell surface.Components are not drawn to scale.


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