Figure 512

Electron micrograph of an elastic fiber. The elastin (E) of the fiber has a relatively amorphous appearance. The fibrillin microfibrils (arrows) are present at the periphery and within the substance of the fiber. A number of collagen fibrils (C) is also present in this electron micrograph. x40,000.

Elastic material is a major extracellular substance in vertebral ligaments, larynx, and elastic arteries

In elastic ligaments, the elastic material consists of thick fibers interspersed with collagen fibers. Examples of this material are found in the ligamenta flava of the vertebral column and the ligamentum nuchae of the neck. Finer fibers are present in elastic ligaments of the vocal folds of the larynx.

In elastic arteries, the elastic material is in the form of fenestrated lamellae, sheets of elastin with gaps or openings. The lamellae are arranged in concentric layers between layers of smooth muscle cells. Like the collagen fibers in the tunica media of blood vessel walls, the elastic material of arteries is produced by smooth muscle cells, not by fibroblasts. In contrast to elastic fibers, microfibrils are not found in the lamellae. Only the amorphous elastin component is seen in electron micrographs.

Elastin is synthesized by the same pathway as collagen

As noted, elastic fibers are produced by fibroblasts. Elastin synthesis parallels collagen production; in fact, both processes can occur simultaneously in a cell. The orderly modification and assembly of procollagen and proelastin, as well as the synthesis of other connective tissue components, are controlled by signal peptides that are built into the beginning of the polypeptide chains of each of the molecules.

Signal peptides can be compared to the airline tags on luggage. Just as the tags ensure that baggage moves correctly from one aircraft to another at airports, so signal peptides ensure that the components of procollagen and proelastin remain separate and properly identified as they pass through the organelles of the cell. During this transit, a series of synthetic events and posttranslational modifications occur before the polypeptides ultimately arrive at their proper destination.

^ ground substance

Ground substance occupies the space between the cells and fibers

Ground substanceis a viscous, clear substance with a slippery feelTTt has a high water content and has little morphologic structure. In the light microscope, ground substance appears amorphous in sections of tissue preserved by freeze drying or in frozen sections stained with basic dyes or by the PAS method. In routine H&E preparations, ground substance is always lost because of its extraction during fixation and dehydration of the tissue. The result is an empty background; only cells and fibers are evident. Thus, in most histologic preparations, the appearance of ground substance—or its lack of appearance—belies its functional importance. Ground substance permits diffusion of oxygen and nutrients between the microvasculature and cellular components of the tissue.

Ground substance consists largely of proteoglycans and hyaluronic acid

Ground substance consists predominately of proteogly-cans, very large macromolecules composed of a core protein to which glycosaminoglycan molecules are covalently bound, Glycosaminoglycans (GAGs) are long-chain polysaccharides composed of repeating disaccharide units. They are named for glucosamine, a hexosamine sugar that is present in each disaccharide.

Proteoglycans and GAGs are responsible for the physical properties of ground substance

GAGs are highly negatively charged because of the sulfate and carboxyl groups located on many of the sugars, hence their propensity for staining with basic dyes. The high density of negative charges also attracts water, forming a hydrated gel. The gel-like composition of the ground substance permits rapid diffusion of water-soluble molecules bût~infrït^s movement of large molécules and bacteria. In addition, proteoglycans contain binding sites for many growth factors, such as transforming growth factor /3 (TGF-/3). The binding of growth factors to proteoglycans may cause either their local aggregation or dispersion, which in turn either inhibits or enhances the movement of migrating macromolecules, microorganisms, or metastatic cancer cells in the extracellular environment.

Based on differences in specific sugar residues, the nature of their linkages, and the degree of sulfation, a family of seven distinct GAGs is recognized. They are listed and partially characterized in Table 5.4. Several of these proteoglycans are modified by connective tissue cells after their synthesis. For example, heparin is formed by enzymatic cleavage of heparan sulfate; dermatan sulfate is similarly modified from chondroitin sulfate.

The GAG hyaluronic acid (HA) deserves special note because it d[ffers.irom the other GAGs in several respects. It is an exceedinglyJ_o.ng, rigid molecule composed of a carbohydrate chain of thousands of sugars, rather than the several hundred or fewer sugars found in other GAGs. Also, HA is n^t^covcdently bound to pr_o£ein tojorma^pro-teoglycan. By means of special link proteins, however,-proteoglycans indirectly bind to HA, forming giant macromolecules, as in the ground substance of cartilage (Fig. 5.13). The swelling pressure, or turgor, that occurs in these giant hydrophilic macromolecules accounts for the ability of cartilage to resist compression without inhibiting flexibility.

s? extracellular matrix

The extracellular matrix is a complex structural network that includes fibrous proteins, proteoglycans, and several glycoproteins

The current view of the extracellular components of connective tissue and their functional role reveals a dynamic system in which fibers, proteoglycans—some belonging to the ground substance and others associated with surfaces— and specific glycoproteins such as fibronectin and laminin interact with the other components. These structures compose the extracellular matrix.

The attachment of the fibroblast to the extracellular matrix has functional implications

Tissue culture studies reveal that fi^roblasts__are__an-chored tightly to matrix elements and that these attach-

TABLE 5.4. Glycosaminoglycans

Name

Hyaluronic acid Chondroitin 4-sulfate Chondroitin 6-sulfate Dermatan sulfate Keratan sulfate

Heparan sulfate

Heparin

Approximate Molecular Weight (Da)

1,000,000 25,000 25,000 35,000 10,000

15,000

40,000

Disaccharide Composition

D-Glucuronic acid + A/-acetylglucosamine

D-Glucuronic acid + ^-acetylgalactosamine 4-sulfate

D-Glucuronic acid + /V-acetylgalactosamine 6-sulfate

L-lduronic acid + ^-acetylgalactosamine 4-sulfate

Galactose or galactose 6-sulfate + A/-acetylglucosamine 6-sulfate

Glucuronic acid or L-iduronic acid 2-sulfate + /V-sulfamylglucosamine or /V-acetylglucosamine

Glucuronic acid or L-iduronic acid 2-sulfate + /V-sulfamylglucosamine or A/-acetylglucosamine 6-sulfate

link protein hyaluronic acid

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