7. Cartilage

matrix of hyaline cartilage

(1 ) The matrix is composed of an amorphous ground substance containing proteoglycan aggregates and chondronectin, in which type II collagen is embedded (2) The matrix that is adjacent to chondrocytes is called the territorial matrix. This part of the matrix is poor in collagen but rich in proteoglycans, and it stains more deeply than does the interterritorial matrix.

Collagen molecules in hyaline cartilage

Four types of collagen participate in the formation of a three-dimensional meshwork of the relatively thin (20-nm diameter) and short matrix fibrils. Type II collagen constitutes the bulk of the fibrils (see Fig. 7.2); type IX collagen facilitates fibril interaction with the matrix proteoglycan molecules; type XI collagen regulates the fibril size; and type X collagen organizes the collagen fibrils into a three-dimensional hexagonal lattice that is crucial to its successful mechanical function. In addition, type VI collagen is also found in the matrix, mainly at the periphery of the chondrocytes where it helps to attach these cells to the matrix framework. Because types II, VI, IX, X, and XI are found in significant amounts only in the cartilage matrix, they are referred to as cartilage-specific collagen molecules. (Review the types of collagen in Table 6.2.)

Proteoglycans in hyaline cartilage

The ground substance of hyaline cartilage contains three kinds of glycosaminoglycans: hyaluronan, chondroitin sulfate, and keratan sulfate. As in loose connective tissue matrix, the chondroitin and keratan sulfate of the cartilage matrix are joined to a core protein to form a proteoglycan monomer. The most important proteoglycan monomer in hyaline cartilage is aggrecan. It has a molecular weight of 250 kDa. Each molecule contains about 100 chondroitin sulfate chains and as many as 60 keratan sulfate molecules. Because of the presence of the sulfate groups, aggrecan molecules have a large negative charge with an affinity for water molecules. Each linear hyaluronan molecule is associated with a large number of aggrecan molecules (more than 300), which are bound to the hyaluronan by link proteins at the N terminus of the molecule to form large proteoglycan aggregates. These highly charged proteoglycan aggregates are bound to the collagen matrix fibrils by electrostatic interactions and multi adhesive glycoproteins (Fig. 7.3). The entrapment of these aggregates within the intricate matrix of collagen fibrils is responsible for the unique biomechanical properties of hyaline cartilage. Cartilage matrix also contains other proteoglycans (e.g., decorin, biglycan, and fibromodulin). These proteoglycans do not form aggregates but bind to other molecules and help stabilize the matrix.

internal remodeling

Throughout life, cartilage undergoes continuous internal remodeling as the cells replace matrix molecules lost through degradation. Normal matrix turnover depends on the ability of the chondrocytes to detect changes in matrix composition. The chondrocytes then respond by synthesizing appropriate types of new molecules. In addition, the matrix acts as a signal transducer for the embedded chondrocytes. Thus, pressure loads applied to the cartilage, as in synovial joints, create mechanical, electrical, and chemical signals that help direct the synthetic activity of the chondrocytes. As the body ages, however, the composition of the matrix changes, and the chondrocytes lose their ability to respond to these stimuli.

isogenous groups of chondrocytes

When the chondrocytes are present in isogenous groups, they represent cells that have recently divided. As the newly divided chondrocytes produce the matrix material that surrounds them, they are dispersed. Th ey also secrete metal- loproteinases, enzymes that degrade cartilage matrix, allow- ing the cells to expand and reposition themselves within the growing isogenous group.

Multiadhesive glycoproteins in hyaline cartilage

also referred to as noncollagenous and nonproteoglycan-linked glycoproteins, influence interactions between the chondrocytes and the matrix molecules. Multiadhesive glycoproteins have clinical value as markers of cartilage turnover and degeneration. Examples of such proteins are anchorin CII ( cartilage annexin V), a small 34 kDa molecule that functions as a collagen receptor on chondrocytes, tenascin, and fibronectin (see Table 6.5, page 176), which also help anchor chondrocytes to the matrix.

Chondrocytes

are mature cartilage cells that are embedded within lacunae in the matrix. (1 ) They arise by differentiation of mesenchymal chondrogenic cells and from chondrogenic cells within the inner layer of the perichondrium into chondroblasts, which are the earliest cells to produce cartilage matrix. Once these cells become totally enveloped by matrix, they are referred to as chondrocytes (see Figure 6.1). (2) Chondrocytes located superficially are ovoid and positioned with their longitudinal axis parallel to the cartilage surface. Those located deeper are more nearly spherical and may occur in groups of four to eight cells (isogenous groups).

Cartilage is a form of

connective tissue composed of cells called chondrocytes and a highly specialized extracellular matrix. The large ratio of glycosaminoglycans (GAGs) to type II collagen fibers in the cartilage matrix permits diffusion of substances between blood vessels in the surrounding connective tissue and the chondrocytes dispersed within the matrix, thus maintaining the viability of the tissue.

Osteoarthritis

degenerative joint disease is one of the most common types of joint diseases. The pathogenesis of osteoarthritis is unknown, but it is related to aging and injury of articular cartilage. Most individuals show some evidence of this disease by age 65. The disease is characterized by chronic joint pain with various degrees of joint deformity and destruction of the articular cartilage. Osteoarthritis commonly affects weight-bearing joints: hips, knees, lower lumbar vertebra, and joints of the hand and foot. There is a decrease in proteoglycan content, which results in a reduction in intercellular water content in the cartilage matrix. Chondrocytes also play an important role in the pathogenesis of osteoarthritis. By producing interleukin-1 (IL -1) and tumor necrosis factor-a (TNF -a), the production of metalloproteinases is stimulated, whereas synthesis of type II collagen and proteoglycans by the chondrocyte is inhibited. In the early stages of the disease, the superficial layer of the articular cartilage is disrupted. Eventually, the destruction of the cartilage extends to the bone, where the exposed subchondral bone becomes a new articular surface. These changes result in a progressive reduction of mobility and increased pain with joint movement. Osteoarthritis has no cure, and treatment focuses on relieving pain and stiffness to allow a greater range of joint movement. Osteoarthritis may stabilize with age, but more often, it slowly progresses with eventual long-term disability.

Perichondrium

is a layer of dense, irregular connective tissue that surrounds hyaline cartilage except at articular surfaces. (1 ) It consists of -an outer fibrous layer containing type I collagen, fibroblasts, and blood vessels and -an inner cellular layer containing chondrogenic cells and chondroblasts. (2) It provides the nearest blood supply to the avascular cartilaginous tissue.

Territorial Matrix (hyaline cartilage) TM

is a region that is more removed from the immediate vicinity of the chondrocytes. It surrounds the isogenous group and contains a randomly arranged network of type II collagen fibrils with smaller quantities of type IX collagen. It also has a lower concen- tration of sulfated proteoglycans and stains less intensely than the capsular matrix.

interterritorial matrix IM

is a region that surrounds the territorial matrix and occupies the space between groups of chondrocytes.`

Capsular (pericellular) matrix P

is a ring of more densely staining matrix located immediately around the chondrocyte (see Fig. 7.4). It contains the highest concentration of sulfated proteoglycans, hyaluronan, biglycans, and several multiadhesive glycoproteins (e.g., fibronectin, decorin, and laminin). The capsular matrix contains almost exclusively type VI collagen fibrils that form a tightly woven enclosure around each chondrocyte. Type VI collagen binds to integrin receptors on the cell surface and anchors the chondrocytes to the matrix. A higher concentration of type IX collagen is also present in the capsular matrix.

Rheumatoid arthritis

is a very severe form of arthritis, where the immune system attacks the joint, including the cartilage, bone, and the synovial membrane. If left untreated, it may destroy the joint, including the cartilage and the bone.

Cartilage

is an avascular specialized fibrous connective tissue. It has a firm extracellular matrix that is less pliable than that of connective tissue proper, and it contains chondrocytes embedded in matrix

Histogenesis of hyaline cartilage

is similar to that of elastic cartilage and fibrocartilage and is affected by certain hormones and vitamins (Table 7.2). It occurs by the following two processes: a. Interstitial growth results from cell division of preexisting chondrocytes. This type of growth occurs only during the early stages of cartilage formation and in articular cartilage and the epiphyseal plates of long bones. b. AppositionaI growth results from differentiation of chondrogenic cells in the perichondrium. This type of growth results in the formation of chondroblasts and/or new chondrocytes, which elaborate a new layer of cartilage matrix at the periphery.

Hyaline cartilage

is the most abundant cartilage in the body, and it also serves as a temporary skeleton in the fetus until it is replaced by bone.

Fibrocartilage

lacks an identifiable perichondrium. It is characterized by alternating rows of fibroblast-derived chondrocytes surrounded by scant matrix and thick parallel bundles of type I collagen fibers. Fibrocartilage is located in areas where support and tensile strength are required and where tissues are exposed to compressive and shear forces. It is located in the intervertebral disks, menisci of the knees, sternoclavicular joints, and the pubic symphysis.

Chondroblasts

manufacture the cartilage matrix through which nutrients and waste materials pass to and from the cells, respectively. These cells contain an extensive Golgi complex, abundant rough endoplasmic reticulum (RER), lipid droplets, and glycogen. Mesenchymal cells can be induced to become secreting chondroblasts in the proper environment, but if removed and grown as a monolayer in a low-density substrate, they will discontinue secreting cartilage matrix, become fibroblast-like, and secrete type I rather than type II collagen.

In early fetal development, hyaline cartilage is the precursor of bones that develop by the process of

of endochondral ossification During the developmental process, in which most of the cartilage is replaced by bone, residual cartilage at the proximal and distal end of the bone serves as growth sites called epiphyseal growth plates (epiphyseal discs). This cartilage remains functional as long as the bone grows in length

Arthritis

one of the processes of aging, is the degeneration of hyaline cartilage, especially as it covers the articulating surfaces of the members of bony joints. Over time, this causes joint pain, redness, swelling, stiffness, and restricts joint mobility.

Elastic cartilage

possesses a perichondrium and is nearly identical to hyaline cartilage except for a network of elastic fibers, which impart a yellowish color. Although it contains type II collagen, it is less prone to degeneration than hyaline cartilage and does not calcify in aging. It is located in areas where flexible support is required. Elastic cartilage exists as in the cartilage of the auditory tube, external ear, and epiglottis.

Cartilage functions

primarily to support soft tissues and assists in the development and growth of long bones.

The network of collagen type II fibers is not only responsible for hyaline cartilage shape and its tensile strength but also

provides a framework to resist the swelling pressure from aggrecan molecules.

Surrounding the cartilage is

the perichondrium housing chondroblasts and chondrogenic cells

Chondrogenesis

the process of cartilage development, begins with the aggregation of chondroprogenitor mesenchymal cells to form a mass of rounded, closely apposed cells. The site of hyaline cartilage formation is recognized initially by an aggregate of mesenchymal or ectomesenchymal cells known as a chondrogenic nodule. Expression of transcription factor SOX-9 triggers differentiation of these cells into chondroblasts, which then secrete cartilage matrix (expression of SOX-9 coincides with secretion of type II collagen)

Three types of cartilage that differ in appearance and mechanical properties are distinguished on the basis of characteristics of their matrix:

• Hyaline cartilage is characterized by a matrix containing type II collagen fibers, GAGs, proteoglycans, and multi-adhesive glycoproteins. • Elastic cartilage is characterized by elastic fibers and elastic lamellae in addition to the matrix material of hyaline cartilage. • Fibrocartilage is characterized by abundant type I collagen fibers as well as the matrix material of hyaline cartilage.

In adults, the articular cartilage is 2- to 5-mm thick and is divided into four zones (Fig. 7.10)

• The superficial (tangential) zone is a pressure-resistant region closest to the articular surface. It contains numerous elongated and flattened chondrocytes surrounded by a condensation of type II collagen fibrils that are arranged in fascicles parallel to the free surface. • The intermediate (transitional) zone lies below the superficial zone and contains round chondrocytes randomly distributed within the matrix. Collagen fibrils are less organized and are arranged in a somewhat oblique orientation to the surface. • The deep (radial) zone is characterized by small, round chondrocytes that are arranged in short columns perpendicular to the free surface of the cartilage. The collagen fibrils are positioned between columns parallel to the long axis of the bone. • The calcified zone is characterized by a calcified matrix with the presence of small chondrocytes. This zone is separated from the deep (radial) zone by a smooth, undulating, heavily calcified line called the tidemark. Above this line, proliferation of chondrocytes within the cartilage lacunae provides the new cells for interstitial growth. In articular cartilage renewal, chondrocytes migrate from this region toward the joint surface.

Repair of hyaline cartilage

◗ Due to its avascular nature, cartilage has limited ability for repair. Repair mostly involves the production of dense connective tissue. ◗ In the aging process, hyaline cartilage is prone to calcifi cation and is replaced by bone.