What Is The Makeup Of The Matrix In The Connective Tissue
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 non exhaustive, merely rather seeks to illustrate the complexity of these tissues, tissues once regarded as relatively uncomplicated structures within a mechanical system. Specific tissues and their special features, such as those of cartilage and bone, are non discussed in depth; instead, the overview emphasizes full general principles that apply across the CT spectrum.
Components of Connective Tissues
Connective tissues and their matrix components make up a big proportion of the total body mass, are highly specialized, and have a diversity of roles. They provide for mechanical support, motion, tissue fluid ship, jail cell migration, wound healing, and—as is condign 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 backdrop of CT are determined primarily by the amount, type, and arrangement of an abundant extracellular matrix (ECM). The ECM consists of 3 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).
Effigy 1.
Master components of connective tissues.
Effigy one.
Principal components of connective tissues.
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 peradventure best exemplified by the prominent aligned fibers of tendons and ligaments. Other collagen fibers, which are far less prominent, include the pocket-size reticular fibers of soft organs such as the liver and the submicroscopic fibrils found in basement membranes. The hit feature of the near prominent collagens is their power 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 private fibers, merely of the straightening of fibers that are packed in diverse three-dimensional arrays. 3,four In contrast, elastic fibers may increase their length past 150%, yet yet render to their previous configuration. 3
The 2nd major component of the ECM is the PGs, a diverse group of soluble macromolecules that accept both structural and metabolic roles. 5,6 They occupy, along with collagen, the interstitial spaces betwixt the cells, form part of basement membranes, and attach to cell surfaces where they function as receptors. 5,6 Of import mechanical functions of PGs include hydration of the matrix, stabilization of collagen networks, and the ability to resist compressive forces, an power all-time exhibited by the PGs of articular cartilage. 5 Hyaluronan (HA), which is technically not a PG considering it lacks a protein core, is particularly important because information technology readily entrains large amounts of h2o and is abundant in hydrated soft loose tissues where repeated motion is required (eg, tendon sheaths and bursae). seven,8
The third group of matrix molecules, the glycoproteins, are ubiquitous in all CTs and, every bit with the PGs, accept both structural and metabolic roles. Their mechanical roles include providing linkage between matrix components and between cells and matrix components.
An of import concept is that the mechanical properties of CT, such as the ability to resist tension, pinch, extensibility, and torsion, are determined by the proportions of the matrix components. In plough, the maintenance of these matrix components and their organization depend on the nature and extent of loading these tissues experience. Generally, tissues with a loftier collagen-fiber content and low amounts of PG resist tensile forces, and those tissues with a loftier 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. This, in turn, produces changes in the ECM and at the level of factor expression, as will exist discussed below.
Table ane.
Major Extracellular Matrix Components and Mechanical Properties of the Common Connective Tissues 1,7, a
| Tissue | Primary Cell Type | Dominant Cobweb | Ascendant PG/GAG and Total GAG Content | Mechanical Properties |
|---|---|---|---|---|
| Tendon | Tenocytes | Collagen | Dermatan sulphate PG ~0.2% of dry weight | Resists tensional forces |
| Articular cartilage | Chondrocytes | Collagen | Chondroitin sulphate PG ~8%–10% of dry weight | Resists compressive forces |
| Bone | Osteoblasts Osteocytes | Collagen | Chondroitin sulphate PG Very pocket-size percent of dry out weight | Resists tension, compression, and torsion (due to hydroxyapatite) |
| Dermis | Fibroblasts | Collagen Elastin | Dermatan and chondroitin sulphate PG ~1% of dry out weight | Resists tension and moderate compression and accomodates stretching |
| Tissue | Principal Cell Blazon | Ascendant Fiber | Dominant PG/GAG and Total GAG Content | Mechanical Properties |
|---|---|---|---|---|
| Tendon | Tenocytes | Collagen | Dermatan sulphate PG ~0.two% of dry weight | Resists tensional forces |
| Articular cartilage | Chondrocytes | Collagen | Chondroitin sulphate PG ~8%–ten% of dry out weight | Resists compressive forces |
| Bone | Osteoblasts Osteocytes | Collagen | Chondroitin sulphate PG Very small percent of dry weight | Resists tension, compression, and torsion (due to hydroxyapatite) |
| Dermis | Fibroblasts | Collagen Elastin | Dermatan and chondroitin sulphate PG ~1% of dry weight | Resists tension and moderate compression and accomodates stretching |
a PG=proteoglycan, GAG=glycosaminoglycan.
Table 1.
Major Extracellular Matrix Components and Mechanical Properties of the Common Connective Tissues 1,7, a
| Tissue | Principal Cell Type | Ascendant Cobweb | Dominant PG/GAG and Total GAG Content | Mechanical Properties |
|---|---|---|---|---|
| Tendon | Tenocytes | Collagen | Dermatan sulphate PG ~0.2% of dry weight | Resists tensional forces |
| Articular cartilage | Chondrocytes | Collagen | Chondroitin sulphate PG ~8%–10% of dry out weight | Resists compressive forces |
| Bone | Osteoblasts Osteocytes | Collagen | Chondroitin sulphate PG Very small percentage of dry weight | Resists tension, compression, and torsion (due to hydroxyapatite) |
| Dermis | Fibroblasts | Collagen Elastin | Dermatan and chondroitin sulphate PG ~ane% of dry weight | Resists tension and moderate compression and accomodates stretching |
| Tissue | Principal Jail cell Type | Dominant Cobweb | Dominant PG/GAG and Total GAG Content | Mechanical Properties |
|---|---|---|---|---|
| Tendon | Tenocytes | Collagen | Dermatan sulphate PG ~0.2% of dry weight | Resists tensional forces |
| Articular cartilage | Chondrocytes | Collagen | Chondroitin sulphate PG ~eight%–10% of dry out weight | Resists compressive forces |
| Bone | Osteoblasts Osteocytes | Collagen | Chondroitin sulphate PG Very modest per centum of dry weight | Resists tension, compression, and torsion (due to hydroxyapatite) |
| Dermis | Fibroblasts | Collagen Elastin | Dermatan and chondroitin sulphate PG ~i% of dry weight | Resists tension and moderate compression and accomodates stretching |
a PG=proteoglycan, GAG=glycosaminoglycan.
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. nine The common structural characteristic 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 power 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 α-chain, is characterized by repeating sequences of iii amino acids, glycine-X-Y (Fig. 2). Considering glycine is the smallest amino acid and occupies the primal core of the triple helix, the repetition of glycine as every third amino acrid is essential for the correct folding of the 3 α-chains into the helical conformation. x,11 Specific collagen types are formed past a diverseness of α-bondage and past variations in the combination of dissimilar α-chains: in some collagens, all iii α-chains are identical; in other collagens, two α-bondage may exist identical; and in some collagens, all 3 α-bondage 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 inter-molecular bonds betwixt the α-chains of adjacent molecules. thirteen
Effigy 2.
Portion of a collagen molecule showing individual alpha chains coiled to form a triple helix. Within each chain, the amino acids are similarly bundled in a helix, with glycine (G) facing the center of the triple helix. The other amino acids are represented by the dots.
Figure 2.
Portion of a collagen molecule showing individual alpha bondage coiled to form a triple helix. Inside each chain, the amino acids are similarly bundled in a helix, with glycine (G) facing the eye of the triple helix. The other amino acids are represented by the dots.
The extremities or terminals of the collagen molecule are nonhelical simply are important for the formation of collagen fibrils and for other nontensile functions, including interactions with other extracellular components. The α-bondage of the principal collagens are synthesized with relatively long extremities, and, afterwards formation of the triple helix, this newly formed collagen molecule (called procollagen) is emitted from the jail 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 nether the light microscope, and bundles of fibers, which are visible to the eye 14 (Fig. 3).
Figure 3.
Representation of collagen synthesis, secretion, and associates. Adapted with permission from Kielty CM, Hopkinson I, Grant ME. Collagen: the collagen family, structure, associates, and system in the extracellular matrix. In: Royce PM, Steinmann BS, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York, NY: Wiley-Liss; 1993:113.
Figure three.
Representation of collagen synthesis, secretion, and assembly. Adjusted with permission from Kielty CM, Hopkinson I, Grant ME. Collagen: the collagen family unit, construction, assembly, and organisation in the extracellular matrix. In: Royce PM, Steinmann BS, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York, NY: Wiley-Liss; 1993:113.
Modifications, variations, and additions to the basic triple-helix conformation requite rise to vi classes of collagens (Tab. 2). 9,10 Of most relevance to physical therapists are the fibril-forming collagens that are institute in tissues (ie, tendons, ligaments) where their primary function is to resist tensile forces and in tissues where at that place is a requirement for resisting tensile loads (ie, dermis, articular cartilage, intervertebral disks [IVDs], os). The other 5 classes of collagen, which are much less abundant but all the same essential to CT functions throughout the body, have a variety of roles. 9,ten These classes of collagen and their roles are summarized in Tabular array 2.
Table 2.
Collagen Types, Location, and Functions 9,10
| Classes of Collagen | Collagen Types | Examples of Location | Functions |
|---|---|---|---|
| FibralForring collagen | I, II, III, Five, Eleven | Tendos, longest, Inter seted disk, bace. cantlage, blood vasseta, demta | I, Two, Iii: rectal lerned on V, XI: control I bed diometaer |
| Fiberl-associated collagens with interrepted triple hassce FACIII | 9, XII, XIV, Sixteen | Coassution bla with brifforring collagen eg, type Nine and Type III in collogen | Intract with other matrix corspondents |
| Cyberspace work fonning collogen | IV | Bossent interbrance | Separate I sure accospterrt Surrounda navy jail cell types leg, anoth nu uscel cells and serve and td Playa a rade In regulation of cell growth, ntgration, and different atten |
| Flanerotous collogen | VI | Uboqtous is connective Result | Brdgeta and aschara lawmaking to char corresponerate of octorocebular indix In pertist In development and small Inrance of Issues |
| Short-chain collogen | 7, Ten, XIII | Seven coreesa and vasouter issue Ten-hydrogen cont age Thirteen blood veasel wall, glocent of k\kilway | Unknown |
| Long-chain collogen | 7 | Bconnent rerrbrance | Secusea basment innerbrance to aerodrome connective Issue matrix |
| Classes of Collagen | Collagen Types | Examples of Location | Functions |
|---|---|---|---|
| FibralForring collagen | I, 2, III, V, Eleven | Tendos, longest, Inter seted deejay, bace. cantlage, claret vasseta, demta | I, II, III: rectal lerned on V, 11: control I bed diometaer |
| Fiberl-associated collagens with interrepted triple hassce FACIII | Nine, XII, XIV, 16 | Coassution bla with brifforring collagen eg, blazon Ix and Blazon Iii in collogen | Intract with other matrix corspondents |
| Cyberspace work fonning collogen | IV | Bossent interbrance | Separate I sure accospterrt Surrounda navy prison cell types leg, anoth nu uscel cells and serve and td Playa a rade In regulation of cell growth, ntgration, and unlike atten |
| Flanerotous collogen | VI | Uboqtous is connective Issue | Brdgeta and aschara code to char corresponerate of octorocebular indix In pertist In development and small Inrance of Issues |
| Short-chain collogen | Seven, X, Thirteen | Seven coreesa and vasouter issue X-hydrogen cont age XIII claret veasel wall, glocent of k\kilway | Unknown |
| Long-chain collogen | Seven | Bconnent rerrbrance | Secusea basment innerbrance to airport connective Issue matrix |
Table two.
Collagen Types, Location, and Functions 9,10
| Classes of Collagen | Collagen Types | Examples of Location | Functions |
|---|---|---|---|
| FibralForring collagen | I, 2, 3, V, Xi | Tendos, longest, Inter seted disk, bace. cantlage, blood vasseta, demta | I, 2, Three: rectal lerned on 5, Eleven: control I bed diometaer |
| Fiberl-associated collagens with interrepted triple hassce FACIII | IX, XII, 14, Sixteen | Coassution bla with brifforring collagen eg, type Nine and Type III in collogen | Intract with other matrix corspondents |
| Net piece of work fonning collogen | IV | Bossent interbrance | Separate I sure accospterrt Surrounda navy cell types leg, anoth nu uscel cells and serve and td Playa a rade In regulation of cell growth, ntgration, and different atten |
| Flanerotous collogen | VI | Uboqtous is connective Issue | Brdgeta and aschara lawmaking to char corresponerate of octorocebular indix In pertist In evolution and small-scale Inrance of Problems |
| Brusque-chain collogen | VII, 10, 13 | VII coreesa and vasouter issue X-hydrogen cont historic period 13 claret veasel wall, glocent of k\kilway | Unknown |
| Long-chain collogen | Seven | Bconnent rerrbrance | Secusea basment innerbrance to airport connective Issue matrix |
| Classes of Collagen | Collagen Types | Examples of Location | Functions |
|---|---|---|---|
| FibralForring collagen | I, II, III, V, 11 | Tendos, longest, Inter seted disk, bace. cantlage, blood vasseta, demta | I, 2, Iii: rectal lerned on Five, XI: control I bed diometaer |
| Fiberl-associated collagens with interrepted triple hassce FACIII | Nine, XII, Fourteen, Sixteen | Coassution bla with brifforring collagen eg, type Nine and Type III in collogen | Intract with other matrix corspondents |
| Net work fonning collogen | IV | Bossent interbrance | Separate I sure accospterrt Surrounda navy jail cell types leg, anoth nu uscel cells and serve and td Playa a rade In regulation of cell growth, ntgration, and unlike atten |
| Flanerotous collogen | VI | Uboqtous is connective Outcome | Brdgeta and aschara code to char corresponerate of octorocebular indix In pertist In development and minor Inrance of Issues |
| Short-chain collogen | VII, X, Xiii | 7 coreesa and vasouter issue Ten-hydrogen cont historic period 13 blood veasel wall, glocent of k\kilway | Unknown |
| Long-chain collogen | Seven | Bconnent rerrbrance | Secusea basment innerbrance to airport connective Event matrix |
Fibril-forming collagens (types I, II, III, V, and XI)
Fibrilforming collagens account for over 70% of the total collagen constitute in the body. x Type I collagen predominates in tissues such as bones, tendons, ligaments, joint capsules, and the annulus fibrosus of the IVD. Blazon Two 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 peculiarly in embryonic tissues and in many developed tissues, such as arteries, peel, and soft organs, where they form reticular fibers. eleven,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 information technology provides early mechanical forcefulness to the newly synthesized matrix. fourteen Every bit fetal development proceeds and equally healing tissue gains in forcefulness, type III fibers are replaced by the stronger type I fibers. 16–eighteen By and large, type I fibrils have a big bore, a feature that correlates with the ability to carry a greater mechanical load. In immature, growing tendons, exercise increases fibril diameter and ultimate tensile strength, but, in the adult, the result of exercise is minimal. Nevertheless, connected tension is necessary to maintain tendon construction because immobilization leads to a loss of tensile strength. xix
Fibrils may as well be formed of more ane type of collagen. Types V and 11 combine with type I and II collagen, respectively, to course heterotypic fibrils, an system that is thought to play a role in determining fibril bore and thereby influence mechanical properties. In full general, the greater the fibril diameter, the smaller the percent of type V and type Eleven 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 past the surface layers of articular cartilage. The arrangement and alignment of the collagen fibers reverberate 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 past muscles to bones. 4 In comparison, blazon I fibers in ligaments are frequently positioned in slightly less parallel arrays, reflecting the need to resist multidirectional forces. For example, in ligaments associated with joints, there is a demand to both limit motion and provide for articulation stability. Collagen as well plays an important role in attaching tendons and ligaments to bone. At these junctions, tendons and ligaments normally widen and requite way to fibrocartilage, a transformation where the aligned fibers originating from the tendon or ligament are separated past other collagen fibers bundled in a 3-dimensional network surrounding rounded cells. 20 This organisation helps to transmit tensile forces onto a broad expanse and reduces the chance of failure under excessive loading.
The type I collagen fibers of bone accept a more circuitous arrangement. Generally, the fibrils are bundled 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 bargain 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, alternate layers of type I fibers link adjacent vertebral bodies and surround the central nucleus pulposus. The fibrous bands are generally aligned at angles of almost 45 degrees from the vertebral axis, an arrangement that provides a machinery 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 level-resistant core. 22
In articular cartilage, the principal collagen fibers are type II, which are arranged to course a network of bands betwixt 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 Half dozen, Ix, and Eleven in a dense capsule organization. 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 let tissues such as skin, the lungs, and claret 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 exist organized into concentric fenestrated sheets (eg, aorta), as small individual fibers (eg, peel, lung), or every bit 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 deed equally a scaffold on which elastin is deposited, but in one case the core elastin is generated, the majority of microfibrils are displaced to the outer aspect of the fiber. Elastin contains two amino acids (ie, desmosine and isodesmosine) that form cross-linkages between adjacent tropoelastin bondage and are important in imparting the rubberband backdrop to elastin. 26 The verbal mechanism of extensibility is non clearly understood, only 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 iv.
Representation of elastic fiber showing elastin core containing and surrounded by microfibrils. Adapted with permission from Cormack DH. Essential Histology. Philadelphia, Pa: JB Lippincott Co; 1993:107.
Figure 4.
Representation of rubberband fiber showing elastin core containing and surrounded by microfibrils. Adapted with permission from Cormack DH. Essential Histology. Philadelphia, Pa: JB Lippincott Co; 1993:107.
Elastic fibers are widely distributed and establish in most organs to varying degrees. They are establish throughout the tracheobronchial tree of the lung and are largely responsible for accommodating pressure changes. 28 The potential energy stored in the rubberband fiber at the finish of inspiration is released during expiration with the consequent assisted recoil of the lung tissue. 28 Similarly, the elastin that is constitute in the walls of arteries withstands the deformation produced past systole, recoils during diastole, and accommodates the hemodynamic stresses that the flow of blood imposes on the avenue wall. 25,29
In the dermis, the elastic fibers provide the characteristic resilience of skin. In that location is a preferential orientation with coiled fibers aligning predominantly at correct 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 peel to recoil. thirty
Elastic fibers are relatively sparse in ligaments, with two 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 rubberband 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 dorsum. The lack of regeneration of functional rubberband fibers in adults is a major problem, and, one time this ability to regenerate is lost, the restoration of normal function is non possible. xxx Elastin, yet, is synthesized past 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, manifestly cannot rebuild the elastic fiber assembly mechanisms, and function is not restored. 27 In general, there is a lack of noesis about the mechanisms of control of elastic fiber germination. 27
Proteoglycans: Hydrators, Stabilizers, and Space Fillers of the Extracellular Matrix
The PGs 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 bear witness 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 upward the disaccharide units, resulting in vi major GAGs: chondroitin sulphates four (CS A) and half-dozen (CS C), keratan sulphate (KS), dermatan sulphate (DS, also known as CS B), heparan sulphate, and HA. Hyaluronan is atypical because information technology is not attached to a poly peptide core, nor is it sulphated. It is usually included nether a discussion of PG, however, because it is the most arable and ubiquitous of the GAGs, and it plays an of import part in bonding to other PGs to form supramolecular complexes.
All GAGs are negatively charged and have a propensity to attract ions, creating an osmotic imbalance that results in the PG-GAG arresting water from surrounding areas. This assimilation helps maintain the hydration of the matrix; the degree of hydration depends on the number of GAG bondage and on the brake placed on PG swelling by the surrounding collagen fibers. half-dozen
The percentage of GAG within CT varies direct 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.two% of dry weight). vii 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 exist divided into accumulation and non-aggregating 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 bondage that bond to the protein core. 5
Aggregating proteoglycans
Accumulation PGs bail to HA. A big 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 bondage attached to the PG core are negatively charged and extend from the cadre protein like the bristles of a bottle brush, a high accuse density is created. This charge density induces an osmotic swelling pressure, resulting in the motility of water into the matrix. Therefore, the PG will tend to swell, merely 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 power to resist compressive forces. Two examples of accumulation 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 office in normal joint function and in skeletal growth. 6,37 A big 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 bondage (approximately thirty) attached to its core protein, simply 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, forth with HA, also functions as an antiadhesive molecule and facilitates cell migration. 38,39
Figure 5.
Representation of an aggrecan monomer with keratan sulphate (KS) and chondroitin sulphate (CS) glycosaminoglycan side bondage attached to the protein cadre. The monomer is attached to hyaluronan and is stabilized at this bounden region by link protein. Numerous monomers attach to hyaluronan to form the large proteoglycan aggregate. Adapted with permission from Heinegard D, Oldberg A. Glycosylated matrix proteins. In: Royce PM, Steinmann B, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York, NY: Wiley-Liss; 1993:193.
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 to hyaluronan and is stabilized at this binding region by link protein. Numerous monomers attach to hyaluronan to form the big proteoglycan aggregate. Adapted with permission from Heinegard D, Oldberg A. Glycosylated matrix proteins. In: Royce PM, Steinmann B, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York, NY: Wiley-Liss; 1993:193.
Nonaggregating proteoglycans
The nonaggregating PGs exercise not bond to HA and often possess only a small number of GAG side chains composed of CS and DS. They announced to play a limited role in withstanding pinch, but they interact with other matrix components and contribute to mechanical stability through interaction with collagen. Decorin, which has ane 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 course an antiparallel array with a neighboring decorin GAG chain extending from an adjacent fibril. 40 Biglycan (2 GAG chains) is besides pocket-size and is found in the matrix betwixt 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, about notably through the binding of growth factors through specific high- and depression-affinity sites on the cadre proteins 41 (Fig. half dozen).
Figure vi.
Representation of biglycan (two glycosaminoglycan side chains) and decorin (i chain), with their similar core proteins. CS=chondroitin sulphate, DS=dermatan sulphate, S-S=disulphide bonds, Y=oligosaccharides. Adjusted with permission from Heinegard D, Oldberg A. Glycosylated matrix proteins. In: Royce PM, Steinmann B, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York, NY: Wiley-Liss; 1993:198. 316.
Figure half-dozen.
Representation of biglycan (2 glycosaminoglycan side chains) and decorin (1 chain), with their similar core proteins. CS=chondroitin sulphate, DS=dermatan sulphate, S-Due south=disulphide bonds, Y=oligosaccharides. Adjusted with permission from Heinegard D, Oldberg A. Glycosylated matrix proteins. In: Royce PM, Steinmann B, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York, NY: Wiley-Liss; 1993:198. 316.
The heparan sulphate PG, syndecan, is fastened to the cell membrane and plays a role in cell growth through binding growth factors, such equally bones fibroblast growth cistron, and acting as a co-receptor. 42,43 Perlecan is establish close to cell surfaces and contributes to the structure of basement membranes. In addition to providing back up, it assists in cellular differentiation. 44
Hyaluronan is an important component of the aggrecan circuitous, 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,viii A relatively rich solution of HA is found in the vitreous sense of humor of the heart, the umbilical cord, and the synovial fluid of joints where its rheological properties are suited for lubrication. 45,46
Function of mechanical forces in determining proteoglycan content and type
In that location is good evidence to show that the maintanence of normal tissue compages requires normal physiological mechanical loading and that CTs answer to changes in practical 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, articulation immobilization or decay results in atrophy of the articular cartilage because of a loss of PG from the matrix. 37 Chiefly, this PG loss following joint immobilization is reversible with a remobilization program. 37,47
Movement lone, without weight bearing, is sufficient to maintain PG content in sheep articular cartilage. 48 The absenteeism of both weight bearing and movement, however, resulted in a large loss (40%) of PG over a period of ane 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 bail to HA and course big aggregates. 49 Every bit a upshot, cartilage may fail to resist compression finer.
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 nether 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 consequence, in part, from the disability of the aggrecan and HA to form a stable complex because of the fragmentation of the link protein. fifty
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 loftier PG content, with a high proportion of chondroitin sulphate PG. 7,51 Cell morphology also changes. 51 In the region nether 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 pressurebearing region. With the awarding of tension, total PG content decreases, but with a ascension in the proportion of dermatan sulphate PG. The return of the tendon to its original position results in a boring (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 alter 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 non 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 jail cell. 53 They are credited with the regulation of many functions, including producing changes in prison cell shape, enhancing prison cell motility, and stimulating cell proliferation and differentiation. 53 Amongst the all-time-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 prison cell attachment to matrix components through, for instance, 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 to a higher place, 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 zipper. 34,53
Changes to the Matrix in Connective Tissue Diseases and Injury
Under normal physiological atmospheric condition, the maintenance of fibers, PG, and glycoproteins is tightly regulated and controlled through a balance between synthesis and deposition. This residual 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 remainder between synthesis and degradation influences normal tissue architecture, impairs organ part, and changes the mechanical properties of the tissues. As a full general ascertainment, 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 besides alters function. A fractional or complete rupture of CT through excessive tensile loading normally occurs in ligaments and tendons and at musculotendinous 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 ordinarily wearisome, taking many months, but follows a generally predicable pattern. 26,59 During the initial stages of healing, rupture sites are bridged by newly synthesized blazon III collagen, but, equally remodeling proceeds, increasing amounts of blazon I collagen predominate and provide greater forcefulness. xx
Concrete exercise too 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 likewise thought to stimulate collagen synthesis and enhance the repair process past causing the collagen fibrils to marshal parallel to the direction of forcefulness 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 at present clear that the cells of the various CTs synthesize a variety of ECM components that human activity not only to underpin the specific biomechanical and functional properties of tissues, merely also to regulate a multifariousness of cellular functions. Importantly for the physical therapist, and equally discussed to a higher place, CTs are responsive to changes in the mechanical surround, both naturally occurring and applied.
The relative proportions of collagens and PGs largely determine the mechanical properties of CTs. The human relationship betwixt the fibril-forming collagens and PG concentration is reciprocal. Connective tissues designed to resist loftier tensile forces are high in collagen and low in total PG content (more often than not dermatan sulphate PGs), whereas CTs subjected to compressive forces have a greater PG content (by and large chondroitin sulphate PGs). Hyaluronan has multiple roles and not but provides tissue hydration and facilitatation of gliding and sliding movements merely 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 vii.
Representation of typical components of the extracellular matrix and their interactions with each other and with receptors on the prison cell surface. Components are not drawn to scale.
Figure 7.
Representation of typical components of the extracellular matrix and their interactions with each other and with receptors on the jail cell surface. Components are not drawn to calibration.
Patients with CT bug affecting movement are frequently examined and treated by concrete therapists. A knowledge of the CT matrix limerick and its relationship to the biomechanical backdrop of these tissues, particularly the anticipated responses to changing mechanical forces, offers an opportunity to provide a rational basis for treatments. The complexity of the interplay among the components, withal, requires that further inquiry be undertaken to determine more than precisely the furnishings of treatments on the construction and role of CTs.
Acknowledgment
We give thanks Mr Arthur Ellis, Section of Anatomy With Radiology, School of Medicine, The Academy of Auckland, for assistance with grooming of the figures.
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© 1999 American Physical Therapy Association
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