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C H A P T E R HYALINE CARTILAGE Matrix 7 Cartilage 129...

C H A P T E R HYALINE CARTILAGE Matrix 7 Cartilage 129 130 FIBROCARTILAGE 134 CARTILAGE FORMATION, GROWTH, & REPAIR 134 Chondrocytes 132 SUMMARY OF KEY POINTS 136 Perichondrium 133 ELASTIC CARTILAGE 133 ASSESS YOUR KNOWLEDGE 136 C artilage is a tough, durable form of supporting con- nective tissue, characterized by an extracellular matrix (ECM) with high concentrations of GAGs and proteoglycans, interacting with collagen and elastic fibers. Structural features of its matrix make cartilage ideal for a vari- tissue, chondrocytes exhibit low metabolic activity. Cartilage also lacks nerves. The perichondrium (Figure 7–2) is a sheath of dense connective tissue that surrounds cartilage in most places, forming an interface between the cartilage and the tissues sup- ety of mechanical and protective roles within the adult skel- ported by the cartilage. The perichondrium harbors the blood eton and elsewhere (Figure 7–1). supply serving the cartilage and a small neural component. Cartilage ECM has a firm consistency that allows the Articular cartilage, which covers the ends of bones in movable tissue to bear mechanical stresses without permanent dis- joints and which erodes in the course of arthritic degenera- tortion. In the respiratory tract, ears, and nose, cartilage tion, lacks perichondrium and is sustained by the diffusion of forms the framework supporting softer tissues. Because of oxygen and nutrients from the synovial fluid. its resiliency and smooth, lubricated surface, cartilage pro- As shown in Figure 7–1, variations in the composition of vides cushioning and sliding regions within skeletal joints the matrix characterize three main types of cartilage: hyaline and facilitates bone movements. As described in Chapter 8, cartilage, elastic cartilage, and fibrocartilage. Important fea- cartilage also guides development and growth of long bones, tures of these are summarized in Table 7–1. both before and after birth. Cartilage consists of cells called chondrocytes (Gr. chondros, cartilage + kytos, cell) embedded in the ECM › › MEDICAL APPLICATION which, unlike connective tissue proper, contains no other cell Many genetic conditions in humans or mice that cause defec- types. Chondrocytes synthesize and maintain all ECM com- tive cartilage, joint deformities, or short limbs are due to ponents and are located in matrix cavities called lacunae. recessive mutations in genes for collagen type II, the aggre- The physical properties of cartilage depend on electro- can core protein, the sulfate transporter, and other proteins static bonds between type II collagen fibrils, hyaluronan, required for normal chondrocyte function. and the sulfated GAGs on densely packed proteoglycans. Its semirigid consistency is attributable to water bound to the negatively charged hyaluronan and GAG chains extending from proteoglycan core proteins, which in turn are enclosed › HYALINE CARTILAGE within a dense meshwork of thin type II collagen fibrils. The Hyaline (Gr. hyalos, glass) cartilage, the most common of the high content of bound water allows cartilage to serve as a three types, is homogeneous and semitransparent in the fresh shock absorber, an important functional role. state. In adults, hyaline cartilage is located in the articular sur- All types of cartilage lack vascular supplies and chon- faces of movable joints, in the walls of larger respiratory pas- drocytes receive nutrients by diffusion from capillaries in sages (nose, larynx, trachea, bronchi), in the ventral ends of ribs, surrounding connective tissue (the perichondrium). In some where they articulate with the sternum, and in the epiphyseal skeletal elements, large blood vessels do traverse cartilage to plates of long bones, where it makes possible longitudinal bone supply other tissues, but these vessels release few nutrients to growth (Figure 7–1). In the embryo, hyaline cartilage forms the the chondrocytes. As might be expected of cells in an avascular temporary skeleton that is gradually replaced by bone. 129 07_Mescher_ch07_p129-137.indd 129 19/03/21 2:39 PM  130 CHAPTER 7 Cartilage FIGURE 7–1 Distribution of cartilage in adults. Cartilage in external ear Extracellular matrix Epiglottis Cartilages in nose Lacuna Larynx (with chondrocyte) Lung Trachea Articular cartilage Perichondrium of a joint Costal cartilage 180x b Hyaline cartilage Cartilage of intervertebral disc Respiratory tract cartilages Perichondrium in the lungs, trachea, Elastic fibers and larynx Pubic symphysis Lacunae (with chondrocytes) Extracellular matrix 80x c Elastic cartilage Meniscus (padlike fibrocartilage in Lacunae knee joint) (with chondrocytes) Extracellular matrix Collagen fibers Articular cartilage Hyaline cartilage of a joint Fibrocartilage 80x Elastic cartilage a d Fibrocartilage (a) There are three types of adult cartilage distributed in many prominent. The photomicrographs show the main features of areas of the skeleton, particularly in joints and where pliable (b) hyaline cartilage, (c) elastic cartilage, and (d) fibrocartilage. support is useful, as in the ribs, ears, and nose. Cartilage sup- Dense connective tissue of perichondrium is shown here with port of other tissues throughout the respiratory tract is also hyaline and elastic cartilage. › › MEDICAL APPLICATION collagen fibrils are barely discernible. Most of the collagen in hyaline cartilage is type II, although small amounts of minor Osteoarthritis, a chronic condition that commonly occurs dur- collagens are also present. ing aging, involves the gradual loss or changed physical proper- Aggrecan (core protein 250 kDa), with approximately ties of the hyaline cartilage that lines the articular ends of bones 150 GAG side chains of chondroitin sulfate and keratan sul- in joints. Joints that are weight-bearing (knees, hips) or heavily fate, is the most abundant proteoglycan of hyaline cartilage. used (wrist, fingers) are most prone to cartilage degeneration. Hundreds of these proteoglycans are bound noncovalently by Fragments released by wear-and-tear to the articular cartilage link proteins to long polymers of hyaluronan, as shown sche- trigger secretion of matrix metalloproteinases and other factors matically in Figure 7–2a and discussed in Chapter 5. These from macrophages in adjacent tissues, which exacerbate dam- proteoglycan complexes biºnd further to the surface of type II age and cause pain and inflammation within the joint. collagen fibrils (Figure 7–2a). Water bound to GAGs in the proteoglycans constitutes up to 60%-80% of the weight of fresh hyaline cartilage. Matrix Another important component of cartilage matrix is the The dry weight of hyaline cartilage is nearly 40% collagen structural multiadhesive glycoprotein chondronectin. Like embedded in a firm, hydrated gel of proteoglycans and struc- fibronectin in other connective tissues, chondronectin binds tural glycoproteins. In routine histology preparations, the pro- specifically to GAGs, collagen, and integrins, mediating the teoglycans make the matrix generally basophilic and the thin adherence of chondrocytes to the ECM. 07_Mescher_ch07_p129-137.indd 130 19/03/21 2:39 PM  Hyaline Cartilage 131 FIGURE 7–2 The structure of cartilage matrix and cells. C H A P T E R Proteoglycan Perichondrium Hyaluronan Perichondrial fibroblast Type II 7 collagen fibril Cartilage Hyaline Cartilage Chondroblast Cartilage Interterritorial matrix Hyaluronan Link protein Chondrocyte Core protein Chondroitin sulfate Territorial matrix Collagen (type II) a b (a) A schematic representation of the most abundant molecules (b) A diagram of the transitional area between the perichondrium in cartilage matrix shows the interaction between type II colla- and the cartilage matrix. Fibroblast-like progenitor cells in the gen fibrils and proteoglycans linked to hyaluronan. Link proteins perichondrium give rise to larger chondroblasts, which divide noncovalently bind the protein core of proteoglycans to the linear and differentiate as chondrocytes. These functional cells produce hyaluronan molecules. The chondroitin sulfate side chains of the matrix components and exist in lacunae surrounded by the matrix. proteoglycan electrostatically bind to the collagen fibrils, forming The ECM immediately around each lacuna, called the territorial a cross-linked matrix. The circled area is shown larger in the lower matrix, contains mostly proteoglycans and sparse collagen; that part of the figure. Physical properties of these matrix components more distant from lacunae, the interterritorial matrix, is richer in produce a highly hydrated, pliable material with great strength. collagen and may be less basophilic. Approximately 75% of the wet weight of hyaline cartilage is water. TABLE 7–1 Important features of the major cartilage types. Hyaline Cartilage Elastic Cartilage Fibrocartilage Main features of the Homogeneous, with type II collagen Type II collagen, aggrecan, and Type II collagen and large areas extracellular matrix and aggrecan darker elastic fibers of dense connective tissue with type I collagen Major cells Chondrocytes, chondroblasts Chondrocytes, chondroblasts Chondrocytes, fibroblasts Typical arrangement Isolated or in small isogenous groups Usually in small isogenous groups Isolated or in isogenous groups of chondrocytes arranged axially Presence of Yes (except at epiphyses and articular Yes No perichondrium cartilage) Main locations or Many components of upper respiratory External ear, external acoustic Intervertebral discs, pubic examples tract; articular ends and epiphyseal meatus, auditory tube; epiglottis and symphysis, meniscus, and certain plates of long bones; fetal skeleton certain other laryngeal cartilages other joints; insertions of tendons Main functions Provides smooth, low-friction surfaces Provides flexible shape and support Provides cushioning, tensile in joints; structural support for of soft tissues strength, and resistance to respiratory tract tearing and compression 07_Mescher_ch07_p129-137.indd 131 19/03/21 2:39 PM  132 CHAPTER 7 Cartilage Staining variations within the matrix reflect local differ- the matrix. In living tissue, chondrocytes fill their lacunae ences in its molecular composition. Immediately surrounding completely. each chondrocyte, the ECM is relatively richer in GAGs than Because cartilage matrix is avascular, chondrocytes collagen, often causing these areas of territorial matrix to respire under low-oxygen tension. Hyaline cartilage cells stain differently from the intervening areas of interterritorial metabolize glucose mainly by anaerobic glycolysis. Nutrients matrix (Figures 7–2b and 7–3). from the blood diffuse to all the chondrocytes from the carti- lage surface, with movements of water and solutes in the carti- Chondrocytes lage matrix promoted by intermittent tissue compression and decompression during body movements. The limits of such Cells occupy relatively little of the hyaline cartilage mass. At diffusion define the maximum thickness of hyaline cartilage, the periphery of the cartilage, young chondrocytes or chon- which usually exists as small, thin plates. droblasts have an elliptic shape, with the long axes parallel to the surface (Figure 7–3). Deeper in the cartilage, they are round and may appear in groups of up to eight cells that origi- › › MEDICAL APPLICATION nate from mitotic divisions of a single chondroblast and are In contrast to other forms of cartilage and most other tissues, called isogenous aggregates. As the chondrocytes become hyaline cartilage is susceptible to partial or isolated regions of more active in secreting collagens and other ECM compo- calcification during aging, especially in the costal cartilage nents, the aggregated cells are pushed apart and occupy sepa- adjacent to the ribs. Calcification of the hyaline matrix, accom- rate lacunae. panied by degenerative changes in the chondrocytes, is a com- Cartilage cells and matrix may shrink slightly during mon part of the aging process and in many respects resembles routine histologic preparation, resulting in both the irreg- endochondral ossification by which bone is formed. ular shape of the chondrocytes and their retraction from FIGURE 7–3 Hyaline cartilage. P P C C M M C P a b (a) The upper part of the photo shows the perichondrium (P), an (b) The thin region of hyaline cartilage shown here has perichon- example of dense connective tissue consisting largely of type I drium (P) on both sides and shows larger lacunae containing collagen. Among the fibroblastic cells of the perichondrium are isogenous groups of chondrocytes (C) within the matrix (M). Such indistinguishable mesenchymal stem cells. There is a gradual groups of two, four, or more cells are produced by mitosis; the transition and differentiation of cells from the perichondrium to cells will separate into individual lacunae as they begin to secrete the cartilage, with some elongated fibroblast-like cells becoming matrix. Territorial matrix immediately around the chondrocytes is larger and more rounded as chondroblasts and chondrocytes (C). more basophilic than interterritorial matrix farther from the cells. These are located within lacunae surrounded by the matrix (M) (X160; H&E) which these cells secreted. (X200; H&E) 07_Mescher_ch07_p129-137.indd 132 19/03/21 2:39 PM  Elastic Cartilage 133 Chondrocyte synthesis of sulfated GAGs and secretion of perichondrium, which is essential for the growth and main- proteoglycans are accelerated by many hormones and growth tenance of cartilage (Figures 7–2b and 7–3). The outer region C H A P T E R factors. A major regulator of hyaline cartilage growth is the of the perichondrium consists largely of collagen type I fibers pituitary-derived protein called growth hormone or somato- and fibroblasts, but an inner layer adjoining the cartilage tropin. This hormone acts indirectly, promoting the endocrine matrix also contains mesenchymal stem cells that provide a release from the liver of insulin-like growth factors, or somato- source for new chondroblasts that divide and differentiate into medins, which directly stimulate the cells of hyaline cartilage. chondrocytes. 7 › › MEDICAL APPLICATION › ELASTIC CARTILAGE Cartilage Elastic Cartilage Cells of cartilage can give rise to either benign (chondroma) or Elastic cartilage is essentially similar to hyaline cartilage slow-growing, malignant (chondrosarcoma) tumors in which except that it contains an abundant network of elastic fibers in cells produce normal matrix components. Chondrosarcomas addition to a meshwork of collagen type II fibrils (Figures 7–4 seldom metastasize and are generally removed surgically. and 7–1c), which give fresh elastic cartilage a yellowish color. With appropriate staining, the elastic fibers usually appear as Perichondrium dark bundles distributed unevenly through the matrix. Except in the articular cartilage of joints, all hyaline car- More flexible than hyaline cartilage, elastic cartilage is tilage is covered by a layer of dense connective tissue, the found in the auricle of the ear, the walls of the external auditory FIGURE 7–4 Elastic cartilage. P C M a b The chondrocytes (C) and overall organization of elastic cartilage flexibility to this type of cartilage. The section in part b includes are similar to those of hyaline cartilage, but the matrix (M) also perichondrium (P) that is also similar to that of hyaline cartilage. contains elastic fibers that can be seen as darker components (a) X160; Hematoxylin and orcein. (b) X180; Weigert resorcin and with proper staining. The abundant elastic fibers provide greater van Gieson. 07_Mescher_ch07_p129-137.indd 133 19/03/21 2:39 PM  134 CHAPTER 7 Cartilage canals, the auditory (Eustachian) tubes, the epiglottis, and the upper respiratory tract. Elastic cartilage in these locations FIGURE 7–5 Fibrocartilage. includes a perichondrium similar to that of most hyaline car- tilage. Throughout elastic cartilage, the cells resemble those of hyaline cartilage both physiologically and structurally. › FIBROCARTILAGE C Fibrocartilage takes various forms in different structures but C is essentially a mingling of hyaline cartilage and dense connec- tive tissue (Figures 7–5 and 7–1d). It is found in intervertebral discs, in attachments of certain ligaments, and in the pubic symphysis—all places where it serves as very tough, yet cush- ioning support tissue for bone. Chondrocytes of fibrocartilage occur singly and often in aligned isogenous aggregates, producing type II collagen and other ECM components, although the matrix around these chondrocytes is typically sparse. Areas with chondrocytes and hyaline matrix are separated by other regions with fibroblasts and dense bundles of type I collagen, which confer extra ten- C sile strength to this tissue (Figure 7–5). The relative scarcity of proteoglycans overall makes fibrocartilage matrix more aci- dophilic than that of hyaline or elastic cartilage. There is no distinct surrounding perichondrium in fibrocartilage. Intervertebral discs of the spinal column are composed primarily of fibrocartilage and act as lubricated cushions and shock absorbers, preventing damage to adjacent vertebrae from abrasive forces or impacts. Held in place by ligaments, interver- tebral discs are discussed further with joints in Chapter 8. Important features of the three major types of cartilage are summarized in Table 7–1. Fibrocartilage varies histologically in different structures, but is always essentially a mixture of hyaline cartilage and dense connective tissue. › CARTILAGE FORMATION, In a small region of intervertebral disc, the axially arranged aggregates of chondrocytes (C) are seen to be surrounded by GROWTH, & REPAIR small amounts of matrix and separated by larger regions with dense collagen and scattered fibroblasts with elongated nuclei All cartilage forms from embryonic mesenchyme in the pro- (arrows). (X250; Picrosirius-hematoxylin) cess of chondrogenesis (Figure 7–6). The first indication of cell differentiation is the rounding up of the mesenchymal cells, which retract their extensions, multiply rapidly, and perichondrium (Figure 7–2b). In both cases, the synthesis become more densely packed together. In general, the terms of matrix contributes greatly to the growth of the cartilage. “chondroblasts” and “chondrocytes,” respectively, refer to the Appositional growth of cartilage is more important during cartilage cells during and after the period of rapid prolifera- postnatal development, although as described in Chapter 8, tion. At both stages, the cells have basophilic cytoplasm rich interstitial growth in cartilaginous regions within long bones in RER for collagen synthesis (Figure 7–7). Production of the is important in increasing the length of these structures. In ECM encloses the cells in their lacunae and then gradually articular cartilage, cells and matrix near the articulating sur- separates chondroblasts from one another. During embryonic face are gradually worn away and must be replaced from development, the cartilage differentiation takes place primar- within, because there is no perichondrium to add cells by ily from the center outward; therefore, the more central cells appositional growth. have the characteristics of chondrocytes, whereas the periph- Except in young children, damaged cartilage undergoes eral cells are typical chondroblasts. The superficial mesen- slow and often incomplete repair, primarily dependent on chyme develops as the perichondrium. cells in the perichondrium, which invade the injured area and Once formed, the cartilage tissue enlarges both by inter- produce new cartilage. In damaged areas, the perichondrium stitial growth, involving mitotic division of preexisting produces a scar of dense connective tissue instead of forming chondrocytes, and by appositional growth, which involves new cartilage. The poor capacity of cartilage for repair or regen- chondroblast differentiation from progenitor cells in the eration is due in part to its avascularity and low metabolic rate. 07_Mescher_ch07_p129-137.indd 134 19/03/21 2:39 PM  Cartilage Formation, Growth, & Repair 135 FIGURE 7–6 Chondrogenesis. 7 C H A P T E R Cartilage Cartilage Formation, Growth, & Repair a b c d The major stages of embryonic cartilage formation, or chondro- various matrix components, which collectively swell with water genesis, are shown here. and form the very extensive ECM. (d) Multiplication of chondro- (a) Mesenchyme is the precursor for all types of cartilage. (b) Mito- blasts within the matrix gives rise to isogenous cell aggregates sur- sis and initial cell differentiation produce a tissue with condensa- rounded by a condensation of territorial matrix. In mature cartilage, tions of rounded cells called chondroblasts. (c) Chondroblasts are this interstitial mitotic activity ceases and all chondrocytes typically then separated from one another again by their production of the become more widely separated by their production of matrix. FIGURE 7–7 Chondrocytes in growing cartilage. This TEM of fibrocartilage shows chondrocytes with abundant are both present in fibrocartilage. Chondrocytes in growing hya- RER actively secreting the collagen-rich matrix. Bundles of colla- line and elastic cartilage have more prominent Golgi complexes gen fibrils, sectioned in several orientations, are very prominent and synthesize abundant proteoglycans in addition to collagens. around the chondrocytes of fibrocartilage. Collagen types I and II (X3750) 07_Mescher_ch07_p129-137.indd 135 19/03/21 2:39 PM  136 CHAPTER 7 Cartilage Cartilage SUMMARY OF KEY POINTS Cartilage is a tough, resilient type of connective tissue that struc- Elastic Cartilage turally supports certain soft tissues, notably in the respiratory Elastic cartilage generally resembles hyaline cartilage in its chondro- tract, and provides cushioned, low-friction surfaces in joints. cytes and major ECM components, but its matrix includes abundant Cells of cartilage, chondrocytes, make up a small percentage of elastic fibers, visible with special stains, which increase the tissue’s the tissue’s mass, which is mainly a flexible mass of extracellular flexibility. matrix (ECM). Elastic cartilage provides flexible support for the external ear as well Chondrocytes are embedded within lacunae surrounded by the as certain structures of the middle ear and larynx; it is always sur- ECM. rounded by perichondrium. Cartilage ECM typically includes collagen as well as abundant proteoglycans, notably aggrecan, which bind a large amount of Fibrocartilage water. Fibrocartilage contains varying combinations of hyaline cartilage Cartilage always lacks blood vessels, lymphatics, and nerves, but it in small amounts of dense connective tissue. is usually surrounded by a dense connective tissue perichondrium Histologically, it consists of small chondrocytes in a hyaline matrix, that is vascularized. usually layered with larger areas of bundled type I collagen with There are three major forms of cartilage: (1) hyaline cartilage, scattered fibroblasts. (2) elastic cartilage, and (3) fibrocartilage. Fibrocartilage provides very tough, strong support at tendon inser- tions and in intervertebral discs and certain other joints. Hyaline Cartilage The ECM of hyaline cartilage is homogenous and glassy, rich Cartilage Formation, Growth, & Repair in fibrils of type II collagen and aggrecan complexes with bound All forms of cartilage form from embryonic mesenchyme. water. Cartilaginous structures grow by mitosis of existing chondro- The ECM has less collagen and more proteoglycan immediately blasts in lacunae (interstitial growth) or formation of new chon- around the lacunae, producing slight staining differences in this droblasts peripherally from progenitor cells in the perichondrium territorial matrix. (appositional growth). Chondrocytes occur singly or in small, mitotically derived isog- Repair or replacement of injured cartilage is very slow and enous groups. ineffective, due in part to the tissue’s avascularity and low Perichondrium is usually present, but not at the hyaline cartilage metabolic rate. of articular surfaces or the epiphyses of growing long bones. Cartilage ASSESS YOUR KNOWLEDGE 1. The molecular basis for the shock absorbing properties of cartilage 5. What is the source of the mesenchymal progenitor cells activated for involves which of the following? the repair of hyaline cartilage of accident-damaged costal cartilages? a. Electrostatic interaction of proteoglycans with type IV collagen a. Perichondrium b. Ability of glycosaminoglycans to bind anions b. Adjacent loose connective tissue c. Noncovalent binding of glycosaminoglycans to protein cores c. Bone of the adjacent rib(s) and sternum d. Sialic acid residues in the glycoproteins d. Chondrocytes of the injured cartilage e. Hydration of glycosaminoglycans e. Stem cells circulating with blood 2. What distinguishes cartilage from most other connective tissues? 6. How does articular cartilage differ from most other hyaline cartilage? a. Its extracellular matrix is rich in collagen. a. It undergoes mainly appositional growth. b. Its predominant cell type is a mesenchymal derivative. b. It contains isogenous groups of chondrocytes. c. Its predominant cell type secretes both fibers and proteoglycans. c. It lacks a perichondrium. d. It lacks blood vessels. d. Its matrix contains aggrecan. e. It functions in mechanical support. e. It is derived from embryonic mesenchyme. 3. Which feature is typical of elastic cartilage? 7. Which step occurs first in chondrogenesis? a. Primary skeletal tissue in the fetus a. Appositional growth b. No identifiable perichondrium b. Conversion of chondroblasts to chondrocytes c. Found in intervertebral discs c. Formation of mesenchymal condensations d. Most widely distributed cartilage type in the body d. Interstitial growth e. Collagen is mainly type II e. Secretion of collagen-rich and proteoglycan-rich matrix 4. Which area in cartilage is relatively collagen-poor and proteoglycan-rich? a. Fibrocartilage b. Territorial matrix c. Epiphyseal plate d. Interterritorial matrix e. Perichondrium 07_Mescher_ch07_p129-137.indd 136 19/03/21 2:39 PM