Basic Histology - Text and Atlas 11th ed

CARTILAGE: INTRODUCTION

Cartilage is characterized by an extracellular matrix enriched with glycosaminoglycans and proteoglycans, macromolecules that interact with collagen and elastic fibers. Variations in the composition of these matrix components produce three types of cartilage adapted to local biomechanical needs.

Cartilage is a specialized form of connective tissue in which the firm consistency of the extracellular matrix allows the tissue to bear mechanical stresses without permanent distortion. Another function of cartilage is to support soft tissues. Because it is smooth surfaced and resilient, cartilage is a shock-absorbing and sliding area for joints and facilitates bone movements. Cartilage is also essential for the development and growth of long bones both before and after birth (see Chapter 8: Bone).

Cartilage consists of cells called chondrocytes (Gr. chondros, cartilage, + kytos, cell) and an extensive extracellular matrixcomposed of fibers and ground substance. Chondrocytes synthesize and secrete the extracellular matrix, and the cells themselves are located in matrix cavities called lacunae. Collagen, hyaluronic acid, proteoglycans, and small amounts of several glycoproteins are the principal macromolecules present in all types of cartilage matrix. Elastic cartilage, characterized by its great pliability, contains significant amounts of the protein elastin in the matrix.

Because collagen and elastin are flexible, the firm gel-like consistency of cartilage depends on electrostatic bonds between collagen fibers and the glycosaminoglycan side chains of matrix proteoglycans. It also depends on the binding of water (solvation water) to the negatively charged glycosaminoglycan chains that extend from the proteoglycan core proteins.

As a consequence of various functional requirements, three forms of cartilage have evolved, each exhibiting variations in matrix composition. In the matrix of hyaline cartilage, the most common form, type II collagen is the principal collagen type (Figure 7–1). The more pliable and distensible elastic cartilage possesses, in addition to collagen type II, an abundance of elastic fibers within its matrix. Fibrocartilage, present in regions of the body subjected to pulling forces, is characterized by a matrix containing a dense network of coarse type I collagen fibers.

Figure 7–1.

Photomicrograph of hyaline cartilage. The extracellular matrix was previously digested with papain to enhance the oriented aggregates of variously disposed collagen type II fibrils. These aggregates appear as black areas. Picrosirius-polarized light stain. Medium magnification.

In all three forms, cartilage is avascular and is nourished by the diffusion of nutrients from capillaries in adjacent connective tissue (perichondrium) or by synovial fluid from joint cavities. In some instances, blood vessels traverse cartilage to nourish other tissues, but these vessels do not supply nutrients to the cartilage. As might be expected of cells in an avascular tissue, chondrocytes exhibit low metabolic activity. Cartilage has no lymphatic vessels or nerves.

The perichondrium (Figures 7–2 and 7–4) is a sheath of dense connective tissue that surrounds cartilage in most places, forming an interface between the cartilage and the tissue supported by the cartilage. The perichondrium harbors the vascular supply for the avascular cartilage and also contains nerves and lymphatic vessels. Articular cartilage, which covers the surfaces of the bones of movable joints, is devoid of perichondrium and is sustained by the diffusion of oxygen and nutrients from the synovial fluid.

Figure 7–2.

Photomicrograph of hyaline cartilage. Chondrocytes are located in matrix lacunae, and most belong to isogenous groups. The upper and lower parts of the figure show the perichondrium stained pink. Note the gradual differentiation of cells from the perichondrium into chondrocytes. H&E stain. Low magnification.

Figure 7–4.

Diagram of the area of transition between the perichondrium and the hyaline cartilage. As perichondrial cells differentiate into chondrocytes, they become round, with an irregular surface. Cartilage (interterritorial) matrix contains numerous fine collagen fibrils except around the periphery of the chondrocytes, where the matrix consists primarily of glycosaminoglycans; this peripheral region is called the territorial, or capsular, matrix.

HYALINE CARTILAGE

Hyaline cartilage (Figure 7–2) is the most common and best studied of the three forms. Fresh hyaline cartilage is bluish-white and translucent. In the embryo, it serves as a temporary skeleton until it is gradually replaced by bone.

In adult mammals, hyaline cartilage is located in the articular surfaces of the movable joints, in the walls of larger respiratory passages (nose, larynx, trachea, bronchi), in the ventral ends of ribs, where they articulate with the sternum, and in the epiphyseal plate, where it is responsible for the longitudinal growth of bone (see Chapter 8: Bone).

Matrix

Forty percent of the dry weight of hyaline cartilage consists of collagen embedded in a firm, hydrated gel of proteoglycans and structural glycoproteins. In routine histology preparations, the collagen is indiscernible for two reasons: the collagen is in the form of fibrils, which have submicroscopic dimensions; and the refractive index of the fibrils is almost the same as that of the ground substance in which they are embedded. Hyaline cartilage contains primarily type II collagen (Figure 7–1). However, small amounts of collagen types IX, X, XI, and others are frequently present.

Cartilage proteoglycans contain chondroitin 4-sulfate, chondroitin 6-sulfate, and keratan sulfate, covalently linked to core proteins. Up to 200 of these proteoglycans are noncovalently associated with long molecules of hyaluronic acid, forming proteoglycan aggregates that interact with collagen (Figure 7–3). The aggregates can be up to 4 m in length. Structurally, proteoglycans resemble bottlebrushes, the protein core being the stem and the radiating glycosaminoglycan chains the bristles.

Figure 7–3.

Schematic representation of molecular organization in cartilage matrix. Link proteins noncovalently bind the protein core of proteoglycans to the linear hyaluronic acid molecules. The chondroitin sulfate side chains of the proteoglycan electrostatically bind to the collagen fibrils, forming a cross-linked matrix. The oval outlines the area shown larger in the lower part of the figure.

The high content of solvation water bound to the negative charges of glycosaminoglycans acts as a shock absorber or biomechanical spring; this is of great functional importance, especially in articular cartilages (see Chapter 8: Bone).

In addition to type II collagen and proteoglycan, an important component of cartilage matrix is the structural glycoprotein chondronectin, a macromolecule that binds specifically to glycosaminoglycans and collagen type II, mediating the adherence of chondrocytes to the extracellular matrix. The cartilage matrix surrounding each chondrocyte is rich in glycosaminoglycan and poor in collagen. This peripheral zone, called the territorial, or capsular, matrix, stains differently from the rest of the matrix (Figures 7–2 and 7–4).

Perichondrium

Except in the articular cartilage of joints, all hyaline cartilage is covered by a layer of dense connective tissue, the perichondrium, which is essential for the growth and maintenance of cartilage (Figures 7–2 and 7–4). It is rich in collagen type I fibers and contains numerous fibroblasts. Although cells in the inner layer of the perichondrium resemble fibroblasts, they are chondroblasts and easily differentiate into chondrocytes.

Chondrocytes

At the periphery of hyaline cartilage, young chondrocytes have an elliptic shape, with the long axis parallel to the surface. Farther in, they are round and may appear in groups of up to eight cells originating from mitotic divisions of a single chondrocyte. These groups are called isogenous (Gr. isos, equal, + genos, family).

Cartilage cells and the matrix shrink during routine histological preparation, resulting in both the irregular shape of the chondrocytes and their retraction from the capsule. In living tissue, and in properly prepared sections, the chondrocytes fill the lacunae completely (Figure 7–5).

Figure 7–5.

Electron micrograph of fibrocartilage from a young animal, showing three chondrocytes in their lacunae. Note the abundance of rough endoplasmic reticulum. Chondrocytes synthesize the cartilage matrix. Fine collagen fibers, sectioned in several places, are prominent around the chondrocytes. x3750.

Chondrocytes synthesize collagens and the other matrix molecules.

Because cartilage is devoid of blood capillaries, chondrocytes respire under low oxygen tension. Hyaline cartilage cells metabolize glucose mainly by anaerobic glycolysis to produce lactic acid as the end product. Nutrients from the blood cross the perichondrium to reach more deeply placed cartilage cells. Mechanisms include diffusion and transport of water and solute promoted by the pumping action of intermittent cartilage compression and decompression. Because of this, the maximum width of the cartilage is limited.

Chondrocyte function depends on a proper hormonal balance. The synthesis of sulfated glycosaminoglycans is accelerated by growth hormone, thyroxin, and testosterone and is slowed by cortisone, hydrocortisone, and estradiol. Cartilage growth depends mainly on the hypophyseal growth hormone somatotropin. This hormone does not act directly on cartilage cells but promotes the synthesis of somatomedin C in the liver. Somatomedin C acts directly on cartilage cells, promoting their growth.

MEDICAL APPLICATION

Cartilage cells can give rise to benign (chondroma) or malignant (chondrosarcoma) tumors.

Histogenesis

Cartilage derives from the mesenchyme (Figure 7–6). The first modification observed is the rounding up of the mesenchymal cells, which retract their extensions, multiply rapidly, and form mesenchymal condensations of chondroblasts. The cells formed by this direct differentiation of mesenchymal cells, now called chondroblasts, have a ribosome-rich basophilic cytoplasm. Synthesis and deposition of the matrix then begin to separate the chondroblasts from one another. During development, the differentiation of cartilage takes place from the center outward; therefore, the more central cells have the characteristics of chondrocytes, whereas the peripheral cells are typical chondroblasts. The superficial mesenchyme develops into the perichondrium.

Figure 7–6.

Histogenesis of hyaline cartilage. A: The mesenchyme is the precursor tissue of all types of cartilage. B: Mitotic proliferation of mesenchymal cells gives rise to a highly cellular tissue. C: Chondroblasts are separated from one another by the formation of a great amount of matrix. D: Multiplication of cartilage cells gives rise to isogenous groups, each surrounded by a condensation of territorial (capsular) matrix.

Growth

The growth of cartilage is attributable to two processes: interstitial growth, resulting from the mitotic division of preexisting chondrocytes, and appositional growth, resulting from the differentiation of perichondrial cells. In both cases, the synthesis of matrix contributes to the growth of the cartilage. Interstitial growth is the less important of the two processes. It occurs only during the early phases of cartilage formation, when it increases tissue mass by expanding the cartilage matrix from within. Interstitial growth also occurs in the epiphyseal plates of long bones and within articular cartilage. In the epiphyseal plates, interstitial growth is important in increasing the length of long bones and in providing a cartilage model for endochondral bone formation (see Chapter 8: Bone). In articular cartilage, as the cells and matrix near the articulating surface are gradually worn away, the cartilage must be replaced from within, since there is no perichondrium there to add cells by apposition. In cartilage found elsewhere in the body, interstitial growth becomes less pronounced, as the matrix becomes increasingly rigid from the cross-linking of matrix molecules. Cartilage then grows in girth only by apposition. Chondroblasts of the perichondrium proliferate and become chondrocytes once they have surrounded themselves with cartilaginous matrix and are incorporated into the existing cartilage (Figures 7–2 and 7–4).

Degenerative Changes

MEDICAL APPLICATION

In contrast to other tissues, hyaline cartilage is more susceptible to degenerative aging processes. Calcification of the matrix, preceded by an increase in the size and volume of the chondrocytes and followed by their death, is a common process in some cartilage. Asbestiform degeneration, frequent in aged cartilage, is due to the formation of localized aggregates of thick, abnormal collagen fibrils.

Poor Regeneration of Cartilage Tissue

Except in young children, damaged cartilage regenerates with difficulty and often incompletely, by activity of the perichondrium, which invades the injured area and generates new cartilage. In extensively damaged areas—and occasionally in small areas—the perichondrium produces a scar of dense connective tissue instead of forming new cartilage.

ELASTIC CARTILAGE

Elastic cartilage is found in the auricle of the ear, the walls of the external auditory canals, the auditory (eustachian) tubes, the epiglottis, and the cuneiform cartilage in the larynx.

Elastic cartilage is essentially identical to hyaline cartilage except that it contains an abundant network of fine elastic fibers in addition to collagen type II fibrils. Fresh elastic cartilage has a yellowish color owing to the presence of elastin in the elastic fibers (Figure 7–7).

Figure 7–7.

Photomicrograph of elastic cartilage, stained for elastic fibers. Cells are not stained. This flexible cartilage is present, for example, in the auricle of the ear and in the epiglottis. Resorcin stain. Medium magnification.

Elastic cartilage is frequently found to be gradually continuous with hyaline cartilage. Like hyaline cartilage, elastic cartilage possesses a perichondrium.

FIBROCARTILAGE

Fibrocartilage is a tissue intermediate between dense connective tissue and hyaline cartilage. It is found in intervertebral disks, in attachments of certain ligaments to the cartilaginous surface of bones, and in the symphysis pubis. Fibrocartilage is always associated with dense connective tissue, and the border areas between these two tissues are not clear-cut, showing a gradual transition.

Fibrocartilage contains chondrocytes, either singly or in isogenous groups, usually arranged in long rows separated by coarse collagen type I fibers (Figure 7–8). Because it is rich in collagen type I, the fibrocartilage matrix is acidophilic.

Figure 7–8.

Photomicrograph of fibrocartilage. Note the rows of chondrocytes separated by collagen fibers. Fibrocartilage is frequently found in the insertion of tendons on the epiphyseal hyaline cartilage. Picrosirius–hematoxylin stain. Medium magnification.

In fibrocartilage, the numerous collagen fibers either form irregular bundles between the groups of chondrocytes or are aligned in a parallel arrangement along the columns of chondrocytes (Figure 7–8). This orientation depends on the stresses acting on fibrocartilage, since the collagen bundles take up a direction parallel to those stresses. There is no identifiable perichondrium in fibrocartilage.

INTERVERTEBRAL DISKS

Each intervertebral disk is situated between two vertebrae and is held to them by means of ligaments. The disks have two components: the fibrous annulus fibrosus and the nucleus pulposus. The intervertebral disk acts as a lubricated cushion that prevents adjacent vertebrae from being eroded by abrasive forces during movement of the spinal column. The nucleus pulposus serves as a shock absorber to cushion the impact between vertebrae.

The annulus fibrosus has an external layer of dense connective tissue, but it is mainly composed of overlapping laminae of fibrocartilage in which collagen bundles are orthogonally arranged in adjacent layers. The multiple lamellae, with the 90° registration of type I collagen fibers in adjacent layers, provide the disk with unusual resilience that enables it to withstand the pressures generated by impinging vertebrae.

The nucleus pulposus is situated in the center of the annulus fibrosus. It is derived from the embryonic notochord and consists of a few rounded cells embedded in a viscous matrix rich in hyaluronic acid and type II collagen fibrils. In children, the nucleus pulposus is large, but it gradually becomes smaller with age and is partially replaced by fibrocartilage.

Herniation of the Intervertebral Disk

MEDICAL APPLICATION

Rupture of the annulus fibrosus, which most frequently occurs in the posterior region where there are fewer collagen bundles, results in expulsion of the nucleus pulposus and a concomitant flattening of the disk. As a consequence, the disk frequently dislocates or slips from its position between the vertebrae. If it moves toward the spinal cord, it can compress the nerves and result in severe pain and neurological disturbances. The pain accompanying a slipped disk may be perceived in areas innervated by the compressed nerve fibers—usually the lower lumbar region.

REFERENCES

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Eyre DR, Muir H: The distribution of different molecular species of collagen in fibrous, elastic and hyaline cartilages of the pig. Biochem J 1975;51:595.

Hall BK (editor): Cartilage, Vol 1: Structure, Function, and Biochemistry. Academic Press, 1983.

Jasin HE: Structure and function of the articular cartilage surface. Scand J Rheumatol 1995;101:51. [PMID: 7747132]

Junqueira LCU et al: Quantitation of collagen-proteoglycan interaction in tissue sections. Connect Tissue Res 1980;7:91. [PMID: 6444567]

Perka C et al: Matrix-mixed culture: new methodology for chondrocyte culture and preparation of cartilage transplants. J Biomed Mater Res 2000;49:305. [PMID: 10602062]

Reddy AH (editor): Extracellular Matrix Structure and Functions. Liss, 1985.

Stockwell RA: Biology of Cartilage Cells. Cambridge University Press, 1979.

Zambrano NZ et al: Collagen arrangement in cartilages. Acta Anat 1982;113:26. [PMID: 7113642]



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