Proteoglycans Have Numerous Functions

As indicated above, proteoglycans are remarkably complex molecules and are found in every tissue of the body, mainly in the ECM or "ground substance." There they are associated with each other and also with the other major structural components of the matrix, collagen and elastin, in quite specific manners. Some proteoglycans bind to collagen and others to elastin. These interactions are important in determining the structural organization of the matrix. Some proteogly-cans (eg, decorin) can also bind growth factors such as

TGF-P, modulating their effects on cells. In addition, some of them interact with certain adhesive proteins such as fibronectin and laminin (see above), also found in the matrix. The GAGs present in the proteoglycans are polyanions and hence bind polycations and cations such as Na+ and K+. This latter ability attracts water by osmotic pressure into the extracellular matrix and contributes to its turgor. GAGs also gel at relatively low concentrations. Because of the long extended nature of the polysaccharide chains of GAGs and their ability to gel, the proteoglycans can act as sieves, restricting the passage of large macromolecules into the ECM but allowing relatively free diffusion of small molecules. Again, because of their extended structures and the huge macromolecular aggregates they often form, they occupy a large volume of the matrix relative to proteins.

A. Some Functions of Specific

GAGs & Proteoglycans_

Hyaluronic acid is especially high in concentration in embryonic tissues and is thought to play an important role in permitting cell migration during morphogenesis and wound repair. Its ability to attract water into the extracellular matrix and thereby "loosen it up" may be important in this regard. The high concentrations of hyaluronic acid and chondroitin sulfates present in cartilage contribute to its compressibility (see below).

Chondroitin sulfates are located at sites of calcification in endochondral bone and are also found in cartilage. They are also located inside certain neurons and may provide an endoskeletal structure, helping to maintain their shape.

Both keratan sulfate I and dermatan sulfate are present in the cornea. They lie between collagen fibrils and play a critical role in corneal transparency. Changes in proteoglycan composition found in corneal scars disappear when the cornea heals. The presence of der-matan sulfate in the sclera may also play a role in maintaining the overall shape of the eye. Keratan sulfate I is also present in cartilage.

Heparin is an important anticoagulant. It binds with factors IX and XI, but its most important interaction is with plasma antithrombin III (discussed in Chapter 51). Heparin can also bind specifically to lipoprotein lipase present in capillary walls, causing a release of this enzyme into the circulation.

Certain proteoglycans (eg, heparan sulfate) are associated with the plasma membrane of cells, with their core proteins actually spanning that membrane. In it they may act as receptors and may also participate in the mediation of cell growth and cell-cell communication. The attachment of cells to their substratum in culture is mediated at least in part by heparan sulfate. This proteoglycan is also found in the basement membrane of the kidney along with type IV collagen and laminin

(see above), where it plays a major role in determining the charge selectiveness of glomerular filtration.

Proteoglycans are also found in intracellular locations such as the nucleus; their function in this organelle has not been elucidated. They are present in some storage or secretory granules, such as the chromaffin granules of the adrenal medulla. It has been postulated that they play a role in release of the contents of such granules. The various functions of GAGs are summarized in Table 48-8.

B. Associations With Major Diseases & With Aging_

Hyaluronic acid may be important in permitting tumor cells to migrate through the ECM. Tumor cells can induce fibroblasts to synthesize greatly increased amounts of this GAG, thereby perhaps facilitating their own spread. Some tumor cells have less heparan sulfate at their surfaces, and this may play a role in the lack of adhesiveness that these cells display.

The intima of the arterial wall contains hyaluronic acid and chondroitin sulfate, dermatan sulfate, and he-paran sulfate proteoglycans. Of these proteoglycans, dermatan sulfate binds plasma low-density lipopro-teins. In addition, dermatan sulfate appears to be the major GAG synthesized by arterial smooth muscle cells. Because it is these cells that proliferate in atherosclerotic lesions in arteries, dermatan sulfate may play an important role in development of the atherosclerotic plaque.

Table 48-8. Some functions of glycosaminoglycans and proteoglycans.1

• Act as structural components of the ECM

• Have specific interactions with collagen, elastin, fibronectin, laminin, and other proteins such as growth factors

• As polyanions, bind polycations and cations

• Contribute to the characteristic turgor of various tissues

• Facilitate cell migration (HA)

• Have role in compressibility of cartilage in weight-bearing (HA, CS)

• Play role in corneal transparency (KS I and DS)

• Have structural role in sclera (DS)

• Act as anticoagulant (heparin)

• Are components of plasma membranes, where they may act as receptors and participate in cell adhesion and cell-cell interactions (eg, HS)

• Determine charge-selectiveness of renal glomerulus (HS)

• Are components of synaptic and other vesicles (eg, HS)

1ECM, extracellular matrix; HA, hyaluronic acid; CS, chondroitin sulfate; KS I, keratan sulfate I; DS, dermatan sulfate; HS, heparan sulfate.

In various types of arthritis, proteoglycans may act as autoantigens, thus contributing to the pathologic features of these conditions. The amount of chon-droitin sulfate in cartilage diminishes with age, whereas the amounts of keratan sulfate and hyaluronic acid increase. These changes may contribute to the development of osteoarthritis. Changes in the amounts of cer-

Table 48-9. The principal proteins found in bone.1

Proteins

Collagen type I

Approximately 90% of total bone protein. Composed of two a1(I) and one a2(I) chains.

Collagen type V

Minor component.

Noncollagen proteins

Plasma proteins

Mixture of various plasma proteins.

Proteoglycans2 CS-PG I (biglycan)

Contains two GAG chains; found in other tissues.

CS-PG II (decorin)

Contains one GAG chain; found in other tissues.

CS-PG III

Bone-specific.

Bone SPARC3 protein (osteonectin)

Not bone-specific.

Osteocalcin (bone Gla protein)

Contains y-carboxyglutamate residues that bind to hydroxyap-atite. Bone-specific.

Osteopontin

Not bone-specific. Glycosylated and phosphorylated.

Bone sialoprotein

Bone-specific. Heavily glycosylated, and sulfated on tyrosine.

Bone morphogenetic proteins (BMPs)

A family (eight or more) of secreted proteins with a variety of actions on bone; many induce ectopic bone growth.

Various functions have been ascribed to the noncollagen proteins, including roles in mineralization; however, most of them are still speculative. It is considered unlikely that the noncollagen proteins that are not bone-specific play a key role in mineralization. A number of other proteins are also present in bone, including a tyrosine-rich acidic matrix protein (TRAMP), some growth factors (eg, TGFP), and enzymes involved in collagen synthesis (eg, lysyl oxidase). 2CS-PG, chondroitin sulfate-proteoglycan; these are similar to the dermatan sulfate PGs (DS-PGs) of cartilage (Table 48-11). 3SPARC, secreted protein acidic and rich in cysteine.

Osteoclast Mesenchyme

Newly formed matrix (osteoid)

Osteoclast Mesenchyme

Newly formed matrix (osteoid)

Figure 48-11. Schematic illustration of the major cells present in membranous bone. Osteoblasts (lighter color) are synthesizing type I collagen, which forms a matrix that traps cells. As this occurs, osteoblasts gradually differentiate to become osteo-cytes. (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology: Text & Atlas, 10th ed. McGraw-Hill, 2003.)

Figure 48-11. Schematic illustration of the major cells present in membranous bone. Osteoblasts (lighter color) are synthesizing type I collagen, which forms a matrix that traps cells. As this occurs, osteoblasts gradually differentiate to become osteo-cytes. (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology: Text & Atlas, 10th ed. McGraw-Hill, 2003.)

tain GAGs in the skin are also observed with aging and help to account for the characteristic changes noted in this organ in the elderly.

An exciting new phase in proteoglycan research is opening up with the findings that mutations that affect individual proteoglycans or the enzymes needed for their synthesis alter the regulation of specific signaling pathways in drosophila and Caenorhabditis elegans, thus affecting development; it already seems likely that similar effects exist in mice and humans.

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