The Major Components Of Cartilage Are Type Ii Collagen Certain Proteoglycans

The principal proteins of hyaline cartilage (the major type of cartilage) are listed in Table 48-11. Type II collagen is the principal protein (Figure 48-13), and a number of other minor types of collagen are also present. In

Matrix Molecular Chondroitin Sulfate

Figure 48-13. Schematic representation of the molecular organization in cartilage matrix. Link proteins noncovalently bind the core protein (lighter color) of proteoglycans to the linear hyaluronic acid molecules (darker color). The chondroitin sulfate side chains of the proteoglycan electrostatically bind to the collagen fibrils, forming a cross-linked matrix. The oval outlines the area enlarged in the lower part of the figure. (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology: Text & Atlas, 10th ed. McGraw-Hill, 2003.)

Figure 48-13. Schematic representation of the molecular organization in cartilage matrix. Link proteins noncovalently bind the core protein (lighter color) of proteoglycans to the linear hyaluronic acid molecules (darker color). The chondroitin sulfate side chains of the proteoglycan electrostatically bind to the collagen fibrils, forming a cross-linked matrix. The oval outlines the area enlarged in the lower part of the figure. (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology: Text & Atlas, 10th ed. McGraw-Hill, 2003.)

addition to these components, elastic cartilage contains elastin and fibroelastic cartilage contains type I collagen. Cartilage contains a number of proteoglycans, which play an important role in its compressibility. Aggrecan (about 2 X 103 kDa) is the major proteoglycan. As shown in Figure 48-14, it has a very complex structure, containing several GAGs (hyaluronic acid, chondroitin sulfate, and keratan sulfate) and both link and core proteins. The core protein contains three domains: A, B, and C. The hyaluronic acid binds noncovalently to domain A of the core protein as well as to the link protein, which stabilizes the hyaluronate-core protein interactions. The keratan sulfate chains are located in domain B, whereas the chondroitin sulfate chains are located in domain C; both of these types of GAGs are bound covalently to the core protein. The core protein also contains both O- and N-linked oligosaccharide chains.

The other proteoglycans found in cartilage have simpler structures than aggrecan.

Chondronectin is involved in the attachment of type II collagen to chondrocytes.

Cartilage is an avascular tissue and obtains most of its nutrients from synovial fluid. It exhibits slow but continuous turnover. Various proteases (eg, collage-nases and stromalysin) synthesized by chondrocytes can degrade collagen and the other proteins found in cartilage. Interleukin-1 (IL-1) and tumor necrosis factor a (TNFa) appear to stimulate the production of such proteases, whereas transforming growth factor P (TGFP) and insulin-like growth factor 1 (IGF-I) generally exert an anabolic influence on cartilage.

THE MOLECULAR BASES OF THE CHONDRODYSPLASIAS INCLUDE MUTATIONS IN GENES ENCODING TYPE II COLLAGEN & FIBROBLAST GROWTH FACTOR RECEPTORS

Chondrodysplasias are a mixed group of hereditary disorders affecting cartilage. They are manifested by short-limbed dwarfism and numerous skeletal deformities. A number of them are due to a variety of mutations in the COL2A1 gene, leading to abnormal forms of type II collagen. One example is Stickler syndrome, manifested by degeneration of joint cartilage and of the vitreous body of the eye.

The best-known of the chondrodysplasias is achon-droplasia, the commonest cause of short-limbed dwarfism. Affected individuals have short limbs, nor

Domain A Domain B Domain C

Domain A Domain B Domain C

Proteoglycans Amino Acids

Figure 48-14. Schematic diagram of the aggrecan from bovine nasal cartilage. A strand of hyaluronic acid is shown on the left. The core protein (about 210 kDa) has three major domains. Domain A, at its amino terminal end, interacts with approximately five repeating disaccharides in hyaluronate. The link protein interacts with both hyaluronate and domain A, stabilizing their interactions. Approximately 30 ker-atan sulfate chains are attached, via GalNAc-Ser linkages, to domain B. Domain C contains about 100 chondroitin sulfate chains attached via Gal-Gal-Xyl-Ser linkages and about 40 O-linked oligosaccharide chains. One or more N-linked glycan chains are also found near the carboxyl terminal of the core protein. (Reproduced, with permission, from Moran LA et al: Biochemistry, 2nd ed. Neil Patterson Publishers, 1994.)

Figure 48-14. Schematic diagram of the aggrecan from bovine nasal cartilage. A strand of hyaluronic acid is shown on the left. The core protein (about 210 kDa) has three major domains. Domain A, at its amino terminal end, interacts with approximately five repeating disaccharides in hyaluronate. The link protein interacts with both hyaluronate and domain A, stabilizing their interactions. Approximately 30 ker-atan sulfate chains are attached, via GalNAc-Ser linkages, to domain B. Domain C contains about 100 chondroitin sulfate chains attached via Gal-Gal-Xyl-Ser linkages and about 40 O-linked oligosaccharide chains. One or more N-linked glycan chains are also found near the carboxyl terminal of the core protein. (Reproduced, with permission, from Moran LA et al: Biochemistry, 2nd ed. Neil Patterson Publishers, 1994.)

mal trunk size, macrocephaly, and a variety of other skeletal abnormalities. The condition is often inherited as an autosomal dominant trait, but many cases are due to new mutations. The molecular basis of achondroplasia is outlined in Figure 48-15. Achondroplasia is not a collagen disorder but is due to mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3). Fibroblast growth factors are a family of at least nine proteins that affect the growth and differentiation of cells of mesenchymal and neuroectodermal origin. Their receptors are transmembrane proteins and form a subgroup of the family of receptor tyrosine kinases. FGFR3 is one member of this subgroup and mediates the actions of FGF3 on cartilage. In almost all cases of achondroplasia that have been investigated, the mutations were found to involve nucleotide 1138 and resulted in substitution of arginine for glycine (residue number 380) in the transmembrane domain of the protein, rendering it inactive. No such mutation was found in unaffected individuals. As indicated in Table 48-10, other skeletal dysplasias (including certain craniosynos-tosis syndromes) are also due to mutations in genes encoding FGF receptors. Another type of skeletal dyspla-sia (diastrophic dysplasia) has been found to be due to mutation in a sulfate transporter. Thus, thanks to recombinant DNA technology, a new era in understanding of skeletal dysplasias has begun.

Figure 48-15. Simplified scheme of the causation of achondroplasia (MIM 100800). In most cases studied so far, the mutation has been a G to A transition at nucleotide 1138. In a few cases, the mutation was a G to C transversion at the same nucleotide. This particular nucleotide is a real "hot spot" for mutation. Both mutations result in replacement of a Gly residue by an Arg residue in the transmembrane segment of the receptor. A few cases involving replacement of Gly by Cys at codon 375 have also been reported.

Figure 48-15. Simplified scheme of the causation of achondroplasia (MIM 100800). In most cases studied so far, the mutation has been a G to A transition at nucleotide 1138. In a few cases, the mutation was a G to C transversion at the same nucleotide. This particular nucleotide is a real "hot spot" for mutation. Both mutations result in replacement of a Gly residue by an Arg residue in the transmembrane segment of the receptor. A few cases involving replacement of Gly by Cys at codon 375 have also been reported.

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