Dr. Kevin Yip

Dr Kevin Yip
Orthopaedic Surgeon
MBBS(UK), FRCS(EDIN), FAM(SING), FHKCOS(ORTHO)

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Collagen Chemistry

The molecular structure of collagen has been of considerable interest for more than a century, because it is the principal structural protein (by mass) for all mammals. It constitutes 65% to 80% of the mass by dry weight of such specialized connective tissues as tendons, ligaments, skin, joint capsules, and cartilage.

It is the only protein with significant tensile force–resisting properties with the exception of elastin, the functional role of which is quite different. Therefore, collagen is the key protein in musculoskeletal stability, providing the mechanical properties that impart the “connect” to connective tissue.

The tensile force–resisting properties of cartilage derive from the precise molecular configuration of the collagen macromolecule. This molecule is one of the largest in the body, forming a rodlike structure 300 nm in length and 1.5 nm in diameter.

These rods are termed tropocollagen. They are assembled in a three-dimensional array in the extracellular environment, being influenced, somehow, by environmental stresses and additional biological factors of which the full details regarding their nature are still unclear.

The sum of the extracellular influences somehow affects the orientation and size of fibrils that are assembled from the tropocollagen units. The tropocollagen assembly typically is patterned in a quarter stagger.

The α chains are not identical among species or within a single species. Early data regarding mammalian skin collagen demonstrated two types of α chains, α1 and α2, which were present in a ratio of 2:1. Miller and Matukas were the first to show that cartilage possesses a collagen that is different in composition from that in most fibrous connective tissues.

This collagen contains a different type of α1 chain, which they termed α1, type II. The collagen in most cartilages consists of three such identical chains, and the abbreviated nomenclature is now αl [II]3, or type II collagen.

At least 27 different types of collagen products of 40 genes have been described in vertebrates . These collagens can be divided into two major classes on the basis of their primary structure and supramolecular assembly: the fibril-forming collagens, and the non–fibril-forming collagens.

The fibril-forming collagens include types I, II, III, V, and X. Each of these types has a long, central, triple-helix domain without any interruptions in the glycine-x-y sequence, where x and y are amino acids. The rest of the collagens belong to the non–fibril-forming class. Although they vary in size, they share the feature of having imperfections in the glycine-x-y sequence. Within this class, type IX, XII, and XIV collagens form a subgroup called the fibril-associated collagens with interrupted triple helices (FACIT). They are associated with type I or II collagen fibrils, and they play a role in the interaction of these fibrils with other matrix components.

Although their sizes and primary structures vary, they share several common structural features. Type XVI collagen appears to be a member of this gro. Summaries of the makeup and distribution of the collagen types accepted at present have been provided in several recent review articles.

The significance of the type II collagen to cartilage is not yet known. It is a heteropolymer with type IX collagen molecules covalently linked at the surface and type XI collagen molecules forming a filamentous template at the core. The principal differences between this collagen and the more common type I collagen that is found in fibrous connective tissue involve the number of hydroxylysine molecules and the presence of a small number of residues of cysteine.

The type II collagen fibrils are thinner near the articular surface and the tangential zone than that are in the deeper zones, and the collagen concentration is greater at the surface. Evidence is accumulating that type IX and XI collagens make critical contributions to the organization and mechanical stability of the type II collagen fibrillar network.

Type IX collagen makes up approximately 10% of the collagen protein in fetal mammalian articular cartilage, but the amount decreases to approximately 1% in adult tissue. The molecule also is categorized as a proteoglycan, because it was originally demonstrated in chicks that single site for attachment of chondroitin sulfate exists on the type IX collagen molecule.

Type IX collagen also is characterized by the presence of four globular domains in the triple-helix structure . In bovine articular cartilage, type IX collagen is found on the surface of type II collagen and appears to be linked covalently to at least one molecule of the type II collagen triple helix. From this evidence, type IX collagen is believed to provide a covalent interface between the surface of the type II collagen fibril and the interfibrillar proteoglycan domain.

Another theory is that type IX collagen provides interfibrillar linkages between type II collagen fibrils and, therefore, may enhance the mechanical stability of the fibrillar network.

Type XI collagen makes up approximately 3% of mature articular cartilage collagen. It has a single globular domain on one end of the triple helix, and it is located within the type II collagen fibrils. Diagrams illustrating the Type II/IX/XI collagen heteromer is shown in Figure 3-4. Other fibrous collagens found in articular cartilage are type VI and X collagens. Both have a short helix.

Type X collagen is found only in hypertrophic zones of growth plates. Type VI collagen has a globular domain on each end. Type VI collagen is unique in that it has no aldehyde cross-link and has arginine–glycine–aspartic acid (RGD) sequences in each α chain; these sequences are important in cell attachment. It binds to hyaluronan  and to fibronectin, and it has been identified in the perilacunar matrix surrounding chondrocytes.

The fundamental process of collagen formation the chondroblasts and chondrocytes is nearly identical to its synthesis by the fibroblast and fibrocyte. The collagen turnover in cartilage proceeds at a rate not unlike that seen in connective tissue of the fibrous type.

Because significant collagen synthesis occurs in adult cartilage, the control processes for spatial orientation of the product, although poorly understood, clearly are of crucial importance.

It is a source of frustration to surgeons and their patients that attempts to achieve cartilage repair, as in surgical arthroplasty, do not successfully regenerate cartilage and seldom produce completely satisfactory clinical results.

The collagen fiber architecture of the arthroplasty repair tissue is disordered throughout the deep layers and lacks the membranelike characteristics that are so important to the surface layer of articular cartilage.

These are major factors contributing to the failure of cartilage regeneration. Details regarding the biology of the cartilage repair process are described later in this chapter.

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