Microscopic Anatomy of the Zygapophysial Joints, Intervertebral Discs, and Other Major Tissues of the Back

General Considerations

The articular cartilages lining the superior and inferior articular processes of each Z joint are similar in many respects to the articular cartilage associated with most synovial joints of the body. This means that the articular cartilage lining each of the articular processes of a Z joint is composed of a special variety of hyaline cartilage that is durable, lubricated by synovial fluid, compressible, and also able to withstand large compressive forces (Standring et al., 2008).

Recall that hyaline cartilage is not unique to the Z joints but is widely distributed in the body. In addition to lining the articular facets of Z joints, it also is found in a portion of the vertebral (cartilaginous) end plates of the IVDs, the nose, most of the laryngeal cartilages, C rings of the trachea, primary and secondary bronchi, costal cartilages of ribs, most articular cartilages of joints throughout the body, and the xiphoid process. It is also the type of cartilage present in the epiphyseal cartilage plates of growing long bones. Consequently, hyaline cartilage is essential for the growth and development of long bones before and after birth.

The purposes of Z joint articular cartilage are to protect the articular surfaces of the superior and inferior articular processes by acting as a shock absorber and to allow the articular surfaces to move across one another with little friction. Both functions are carried out efficiently. In fact, the coefficient of friction for typical articular surfaces is less than 0.002, which means that the two surfaces of a typical Z joint glide across each other with much greater ease than they would if they were both made of ice (the coefficient of friction for ice sliding on ice is <0.03) (Whiting, 1998).

The articular cartilage of a single Z joint surface is small; in fact, the lumbar articular surfaces measure approximately 8 × 10 mm (Giles, 1992a, b). The Z joint articular cartilage also is approximately 1 to 2 mm thick (Figs. 14-1, 14-2, and 14-3). The concavity of the cartilage on lumbar superior articular facets is thicker than the periphery of the same surfaces. This is the opposite from that typically found in other joints of the body where the concavity of a joint surface usually is lined by thinner cartilage than that surrounding the concavity.

Z joint articular cartilage is made up of 75% water and 25% solids (Giles, 1992a, b) and consists of cells embedded in an abundant and firm matrix (Fig. 14-4). The cells that produce the cartilage matrix are chondroblasts, and in mature cartilage they are known as chondrocytes (Table 14-1). The matrix consists of an intricate network of collagen fibers surrounded by proteoglycans and glycoproteins. The concentration of these constituents of articular cartilage differs from one part of the joint surface to another and also at different depths from the joint surface (Giles, 1992a, b).

Fresh hyaline cartilage is bluish white and translucent. In stained, fixed preparations, the matrix appears glassy, homogeneous, and smooth. Distributed throughout the matrix are spaces called lacunae, and within each lacuna is a chondrocyte. As with all articular cartilage, that of the Z joints has no nerve supply and no direct blood supply. Chondrocytes must receive nutrients by diffusion across the cartilage matrix from several sources. These sources include the blood vessels within the synovial membrane that is located along the peripheral margin of the nonarticular portion of the cartilage, the synovial fluid, and the blood vessels in the adjacent bone (Standing et al., 2008).

Chondrocytes are found singly in the lacunae. Commonly, especially in cartilage that is actively growing, the lacunae are grouped into clusters of two or more. These clusters are called cell nests or isogenous cell groups (Fig. 14-5). The cells within the nests have arisen from the mitotic activity of a single chondrocyte; therefore the presence of isogenous cell groups signifies interstitial cartilage growth. This is supported by electron microscopic findings revealing that the chondrocytes within a cell nest exhibit a well-developed rough endoplasmic reticulum, a Golgi complex, and a large amount of glycogen and lipid.

Articular cartilage differs from typical hyaline cartilage in that the articular surface does not possess a covering of perichondrium (Giles, 1992b; Standring et al., 2008). Instead the cells of the articular surface appear flat and are closer together than they are farther within the cartilage matrix. In addition, the matrix of the articular surface becomes dense and fibrous. The collagen fibers, which course perpendicular to the articulating surface from deep within the cartilage matrix, curve as they reach the joint surface and become oriented parallel to the free edge of the articular cartilage.

Cartilage Matrix

The cartilage matrix immediately surrounds the lacunae containing the chondrocytes. The matrix of hyaline cartilage consists of collagen (type II) fibers, a small number of elastic fibers, and an amorphous ground substance. The ground substance consists primarily of proteoglycans and glycoproteins. Each of these components of the cartilage matrix contributes to the strength, longevity, and resilience of this tissue.

Ligamentum Flavum

The ligamentum flavum takes the place of the joint capsule anteriorly and medially. As discussed, this ligament passes from the anterior and inferior aspect of the lamina of the vertebra above to the posterior and superior aspect of the lamina of the vertebra below. However, the lateral fibers of this ligament course anterior to the Z joint, attach to its margins, and form its anterior capsule. Synovial extensions, or cysts, protrude out of the Z joint and along the attachment sites of the ligamentum flavum to the adjacent superior and inferior articular processes.

The ligamentum flavum is 80% elastic fibers and 20% collagen fibers. The elastic fibers within the ligamentum flavum prevent it from buckling into the intervertebral foramen (IVF) and vertebral canal, thus sparing the contents of these regions. Degenerative change of the ligamentum flavum can result in elastic fibers being replaced with collagen. This replacement with collagen causes the ligamentum flavum to thicken (up to 10 times its normal width in some instances), which in turn can cause stenosis of the vertebral canal.

However, as described in Chapter 7, many instances of ligamenta flava hypertropy are probably the result of inflammation related to repeated microtears in the ligament. The inflammation then leads to hypertrophic scar formation (fibrosis) (Sairyo et al., 2007).

The ligamentum flavum can also ossify over a long period of time, which can lead to serious vertebral canal stenosis. Ossification of the ligamentum flavum has a higher prevalence in the Asian population than in other racial groups. The ossification process appears to be related to degeneration of the elastic fibers, which in the case of ossification of the ligamentum flavum appears to have a genetic component (Yayama et al., 2007).

Early Connective Tissue (Mesenchyme)

The connective tissue appearing in embryonic and early fetal development is called mesenchyme. When examined under the light microscope, this type of tissue is seen to be composed of large stellate or spindle-shaped cells that are separated by an abundant amount of intercellular substance. Early embryonic mesenchymal tissue does not contain fiber bundles. Instead, it is composed of fine reticular fibrils (type III collagen) embedded in a gelatinous, amorphous ground substance that is rich in glycosaminoglycans. Embryonic mesenchymal tissue is described as a multipotent or pluripotent tissue. This suggests that mesenchymal cells undergo extensive mitosis and are able to develop into many different types of connective tissue and related cells during fetal and adult life.

Mature Connective Tissue

Connective tissue is responsible for maintaining structural interrelationships between tissues and cells, including the tissues and cells of the spine. All connective tissue is composed of cells, extracellular fibers, an amorphous ground substance, and tissue fluid. The extracellular fibers and ground substance form the extracellular matrix. In contrast to other body tissues (e.g., epithelium, muscle), connective tissue contains fewer cells in proportion to the amount of extracellular matrix. Based on the composition of the extracellular matrix, adult connective tissue is classified into three main types: connective tissue proper, cartilage, and bone. The composition of the extracellular matrix varies among these three types. In connective tissue proper the extracellular matrix is soft; in cartilage it is much firmer, partially calcified, but flexible in nature; and in bone the matrix is rigid because of the presence of calcium salts, which are in the form of hydroxyapatite crystals.

Cartilage and bone are specialized types of connective tissue. Three histologic types of cartilage are encountered based on characteristics of the ground substance matrix:

Hyaline cartilage is discussed in the previous section along with the Z joints, and fibrocartilage is discussed with the IVD. There is no elastic cartilage in spinal tissues; therefore this type of cartilage is not discussed in this chapter.

Collagen Synthesis

Collagen is the most important fiber type of connective tissue. Collagen is a major component of connective tissue proper, cartilage, and bone. Collagen fibers are found in abundance throughout the articular capsule and hyaline cartilage of the Z joints and also throughout the IVDs. Collagen fibers are composed of collagen macromolecules, which are the most abundant protein in the human body. Collagen fibers are flexible and strong, and they are made up of a bundle of fine, threadlike subunits called collagen fibrils. Collagen is a stable protein under the physiologic conditions that exist in connective tissue; however, collagen is constantly being degraded and replenished by collagen-secreting cells.

It was believed for many years that collagen synthesis occurred primarily in fibroblasts, chondroblasts, osteoblasts, and odontoblasts; however, recent investigations in collagen biology indicate that many other cell types produce this unique protein. Collagen synthesis has been studied extensively in fibroblasts (Standring et al., 2008). Fibroblasts have the extensive rough endoplasmic reticulum and well-developed Golgi apparatus required of cells actively involved in protein synthesis. Labeled amino acids endocytosed by fibroblasts can be followed autoradiographically to the rough endoplasmic reticulum (rER), later to the Golgi complex, then to the outside of the fibroblast, and eventually to the newly formed collagen fibers. This evidence indicates that the collagen synthesis pathway is similar to that of other proteins. Fibroblasts synthesize collagen de novo and secrete it into the extracellular matrix. Fibroblasts also have the ability to break down collagen with specific degradative enzymes called collagenases.

Collagen is a ubiquitous substance that is extremely important in the integrity of both the Z joints and IVDs. Current research and possibly future treatments (nutritional and pharmacologic) related to these two regions of the spine may involve the individual steps of collagen synthesis. Because of the clinical importance of collagen synthesis, this pathway is discussed briefly here.

Collagen synthesis begins inside cells. However, the final processing and assembly into fibers takes place after collagen building blocks have been secreted outside the manufacturing cells. The intracellular events include synthesis of proalpha chains in the rER, hydroxylation and glycosylation of proalpha chains into triple helices in the Golgi apparatus, and formation of secretory granules (vesicles). The extracellular events include cleavage of extension peptides, fibrillogenesis and cross-linking, and assembly of fibrils into mature fibers (Fig. 14-8). Box 14-1 shows the events (steps) involved in collagen synthesis within the fibroblast (steps 1 through 9) and outside the fibroblast in the extracellular matrix (steps 10 through 12).

The amino acid composition of collagen is one of the features that make collagen such a unique protein. Four amino acids compose most of the polypeptides in the collagen macromolecules. The principal amino acids that make up collagen are glycine (35%), proline (12%), hydroxyproline (10%), and alanine (11%). In the cytoplasm of the fibroblast, approximately 250 to 300 amino acids are combined by polyribosomes associated with rER to form a polypeptide with a molecular weight of 30,000 Da. This step of translation is performed under the control of messenger ribosomal ribonucleic acid (mRNA). Three polypeptide chains are combined into polypeptide alpha triple helices with a molecular weight of approximately 100,000 Da. These triple helices are released into the cisternae of rER (see Box 14-1, steps 1 through 3). Glycine is the third amino acid in each alpha chain of the newly formed triple helix. The amino acid after glycine frequently is proline, and the amino acid preceding the glycine frequently is hydroxyproline. Differences in the chemical structure of the alpha chains are responsible for at least 19 different types of collagen identified to date (Ross et al., 2003). Specifics of the 11 most common types of collagen can be found in Table 14-3.

Several modifications of the polypeptide chains occur within the cisternae of rER and the Golgi apparatus (see Box 14-1, steps 4 to 6, and Fig. 14-8). Disulfide bonds are formed within each polypeptide chain and between adjacent chains. Vitamin C is necessary for the formation of the disulfide bonds, and its absence results in certain types of collagen-related diseases such as scurvy. This bonding gives shape and stability to the triple-helix collagen macromolecule. The structure formed now constitutes a procollagen molecule. The procollagen molecule moves to the exterior of the cell via secretory granules (see Box 14-1, steps 7 to 9, and Fig. 14-8). Further modifications are made outside the cell. For example, enzymes cleave most of the uncoiled amino acids, thereby converting procollagen to tropocollagen molecules. These eventually aggregate to produce collagen fibrils (see Box 14-1, steps 10 to 12). Cross-links between lysine and hydroxylysine are then formed, giving the molecule its tensile strength. Changes in collagen cross-links have been seen in IVD degeneration (Duance et al., 1998).

The tropocollagen molecules are 300 nm long and 1.5 nm in diameter. They consist of three polypeptide chains that are twisted around one another to form a right-handed superhelix with a head and a tail end. Numerous tropocollagen molecules lie end-to-end and also in parallel chains or rows. All the molecules face the same direction, and approximately one fourth of the length of the tropocollagen molecule overlaps between the parallel rows. Therefore a tropocollagen molecule of one row ends approximately one fourth of the distance along the length of another tropocollagen molecule of an adjacent row. This configuration results in a regular 64- to 67-nm periodicity that is clearly visible on an electron micrograph. Figure 14-9 shows collagen fibers within the IVD.

The finest strand of collagen that can be seen with the light microscope is the fibril, which is approximately 0.2 to 0.3 µm in diameter. A fibril is made up of still smaller units that have a diameter of 45 to 100 nm. These are called microfibrils. Newly formed microfibrils are only approximately 20 nm in diameter, and evidence shows that they increase in size with age. Most microfibrils are visible only with the electron microscope and demonstrate the characteristic cross-banding with a periodicity of 64 to 67 nm. The parallel assembly of microfibrils forms fibrils. The fibrils in turn aggregate in bundles to form the thicker collagen fibers. These fibers have a diameter ranging from 1 to 12 µm or more.

Types of Collagen

At present, 19 different types of collagen have been positively identified. They are designated as types I through XIX. Types I to V are the most abundant types of collagen. Types VI to XIX are considered less important because they occur in small quantities. Several of the minor types of collagen (types VI, IX, X, XI, XII, and XIV) are present in small amounts in the IVD (Duance et al., 1998). Table 14-3 lists the characteristics of the 11 most important types of collagen.

Types I, II, and III are arranged as ropelike fibrils and are the main forms of fibrillar collagen. Type I collagen consists of two alpha-1 chains and one alpha-2 chain and represents 90% of all collagen fibers distributed in connective tissue. Because type I fibers resist tensile stresses, their orientation and cross-linking vary according to the local environment. Type I collagen is found in bone, tendon, and the anulus fibrosus (AF) of the IVD. It is also found in the skin and cornea (see Table 14-3).

Type II collagen fibers are small, banded fibrils averaging 20 nm in diameter. They help to form the extracellular matrix of hyaline cartilage, including that of the Z joints and cartilaginous end plates (CEPs) of the IVDs. Type II collagen is the main type of collagen found in the nucleus pulposus (NP) of the IVD. It is also found in elastic cartilage and the cornea and vitreous body of the eye. These fibers demonstrate a high electrostatic attraction for the chondroitin sulfate glycosaminoglycans. Type II collagen contains a higher degree of lysine hydroxylation than type I collagen.

Types III and IV collagen are well distributed throughout the body but are not found to any great extent in Z joints, IVDs, or other spinal tissues, although type III has been found in regions adjacent to spondylosis (Schollmeier, Lahr-Eigen, & Lewandrowski, 2000). The key features of these fibers and collagen types V through XI are listed in Table 14-3.

Ground Substance

The cells and fibers of connective tissue are surrounded by a translucent, fluidic, homogeneous, gel-like matrix called amorphous ground substance (Bloom & Fawcett, 1986). The ground substance exhibits no structural organization that is visible with light microscopy. Extracellular amorphous ground substance plays a vital role in the regulation of tissue nutrition, support, and maintenance of proper water content. Based on chemical analysis, the extracellular ground substance of connective tissue has the physical properties of a viscous solution or thin gel and consists of proteoglycans and glycosaminoglycans of various types. Proteoglycans and glycosaminoglycans are an important part of the hyaline cartilage of the Z joints and the cartilaginous (vertebral) end plates of the IVDs. They are also being studied with regard to the AF and NP of the IVD. Therefore glycosaminoglycans and proteoglycans are discussed in further detail with the articular cartilage of the Z joint (see previous discussion) and with the IVD (see following discussion).

Clinical Considerations

Fluid moves in and out of the NP during the day, providing nutrients to the disc. During sleeping hours, the NP fills with fluid and presses against the AF. Therefore when an individual arises in the morning, the AF is tense and less flexible. This increase in AF tension after approximately 5 hours of rest may render it more vulnerable to injury after the rest.

Sudden movements of the lumbar spine, especially torsion coupled with flexion, can produce small tears in the AF. These tears usually occur in the posterior part of the AF, where the distribution of collagen fibers is less concentrated. Sometimes, tears in the AF may allow some of the soft, jellylike NP to squeeze out into the vertebral canal. This latter condition is known as an extruded IVD (see Chapter 11). IVD extrusion is not as common a cause of back pain as once thought (see Chapter 7). However, the discs can be a source of pain without protrusion or extrusion (Bogduk, 1990). Contrary to previous reports (Malinsky, 1959; Wyke, 1987) that the IVD could not produce pain because it lacks nerve supply, several investigators (Yoshizawa, O’Brien, & Thomas-Smith, 1980; Bogduk et al., 1981) have confirmed that the lumbar discs do have a nerve supply and that nerve fibers and nerve endings have been demonstrated to exist in at least the outer third and possibly as far as the outer half of the AF. Most of these authors conclude that the lumbar disc is supplied with the necessary apparatus for the transmission of nociception, resulting in the subsequent perception of pain. Chapters 2, 7, and 11 discuss the gross anatomy, including the innervation, and the clinical relevance of the IVD (including the AF) in further detail.

The Controversial Role of the Notochord in the Formation of the Nucleus Pulposus

As mentioned, the NP is located in the center of the AF and occupies 35% to 50% of the IVD volume. In children the NP is large and is derived from the notochord (see Fig. 12-12). Gradually the transparent embryonic notochordal cells are replaced by a sparse population of chondrocytes and fibroblasts that originate in the CEP (Kim et al., 2003). In time these cells are partially replaced by fibrocartilage, which makes the NP more opaque and no longer transparent (Mescher, 2010).

Several investigators have proposed that embryonic notochordal cells undergo degeneration and disappear soon after birth and that these cells have no further participation in the formation of the NP. Virchow (1857) wrote that the NP was formed from connective tissue. Luschka (1856, 1857) maintained that both the notochordal cells and the liquefaction of the inner layers of the surrounding connective tissue contributed to the formation of the NP. Peacock (1951) concluded that the NP was produced by mucoid degeneration of notochordal cells, which caused the disappearance of these cells and increased the mucoid matrix. However, Woelf and colleagues (1975) studied enzymes present in the NP and described the presence of enzymes that were associated with PG synthesis and oxidative activity. This indication of PG synthesis led them to conclude that human notochordal cells do contribute to the matrix of the NP in fetal and postnatal life.

Oda and colleagues (1988) found that the NP was composed of tissue derived from the notochord in specimens collected from individuals ranging in age from 1 month to the midteens. They also found a fine fibrous tissue in the NP that was derived from the AF. No notochordal cells were demonstrated in the NP in the specimens that came from individuals 16 to 19 years of age. Also, the NP of the specimens had been replaced by fibrocartilage and dense collagenous fibrous tissue. These findings have been supported by those of Boos and colleagues (2002). Pritzker (1977) and Bishop (1992) suggested that the cells originating from the vertebral CEPs might be responsible for synthesizing the gelatinous matrix of the NP in mature IVDs. Kim and colleagues (2003) found in a rabbit model that the NP changes from having notochordal cells to chondrocyte-like cells. These cells were found to migrate from the adjacent CEP. The CEP chondrocytes began to migrate from the peripheral region of the CEP–NP interface; then the process progressed centrally, changing the notochordal NP into a fibrocartilaginous NP. The NP notochordal cells have also been found to stimulate migration of the CEP chondrocytes (Kim et al., 2009). Therefore notochordal cells probably contribute to the formation, development, and maintenance of the NP and to the migration of CEP chondrocytes into the maturing NP. However, this role dramatically declines as individuals reach ages 11-16 years. After this age, the vertebral end plate may continue to help the few cells left within the NP maintain the PG and collagen composition of the NP.

End Plate Fracture (Intravertebral Herniation, Schmorl’s Nodes)

Hydrostatic loading of the NP of the IVD causes bulges of the nucleus into the CEP. Fracture of the CEP can occur if the compressive force is great enough. CEP fractures, also known as traumatic intravertebral herniations (Fardon, 2001) or Schmorl’s nodes, have been noted in postmortem studies as features of disc degeneration (Vernon-Roberts & Pirie, 1977; Sachs et al., 1987) (see Fig. 14-13).

Schmorl’s nodes, or intravertebral disc herniations, are defined as herniations of the IVD through the CEP and bony end plate (Figs. 14-15 and 14-16; see also Fig. 14-13). They were first described in 1927 by a German pathologist, Christian G. Schmorl. These lesions are believed to be associated with trauma and occur most frequently in the lower thoracic and lumbar regions. Even though trauma is the most likely cause of Schmorl’s node formation, a possible congenital origin, such as notochordal cell “rests” (i.e., pockets of notochordal cells that remain after they are normally displaced by chondrocytes or osteocytes) within the subchondral bone adjacent to the CEP, also has been suggested (Taylor, 1990; Pate, 1991) (notochordal cell rests can be seen as the white-appearing structures in the region of the vertebral bodies adjacent to the IVDs in Fig. 13-8). Such congenital defects could predispose one to a later CEP fracture.

Reported incidence of Schmorl’s nodes ranges from 38% in radiologic studies to 76% in postmortem studies; however, the incidence varies rather dramatically in different populations. For example, the incidence in the Chinese population is 16.4% (Mok et al., 2010). Schmorl’s nodes are more common in the upper (L1-L2 and L2-L3) versus lower lumbar vertebrae (L3-L4 and L4-L5) and are least common at L5-S1 (Mok et al., 2010). Schmorl’s nodes are thought to occur most commonly between the ages of 20 and 40, when the IVD has a relatively high fluid pressure (Chandraraj, Briggs, & Opeskin, 1998). They are also more prevelent in taller and heavier individuals and in males (Mok et al., 2010).

Because the CEP, particularly the region adjacent to the NP, receives sensory innervation (Edgar, 2007), Schmorl’s nodes secondary to end plate fractures are likely a source of pain. In addition, Schmorl’s nodes probably predispose the IVD to early degenerative change, especially when observed in younger age groups. In fact, a dorsolumbar kyphosis, seen in adolescents, may be associated with Schmorl’s nodes. Therefore CEP fractures should be considered a possible etiologic cause when an active adolescent patient has back pain of the thoracolumbar region.

Compression injury frequently results in an end plate fracture. This may completely resolve in some patients, or in others, inflammatory repair processes may extend into the NP and result in disc degradation (see Chapter 7). Such inflammatory disc degradation initiates internal disc disruption, which may become symptomatic. If the AF remains intact, isolated IVD resorption may follow, but if fissures and tears develop in the AF, the degraded nuclear material may extrude (Bogduk, 1990).

Summary of the Normal Aging of the Intervertebral Disc as a Whole

The normal aging (and degeneration) of the IVD is closely related to the number of vessels that reach the IVD, especially the CEP. As the numbers of vessels decrease, and the nutrition provided and waste removed by these vessels decrease, the changes associated with IVD aging and degeneration increase (Brown et al., 1997; Chandraraj, Briggs, & Opeskin, 1998; Horner & Urban, 2001; Boos et al., 2002) (see Fig. 14-17).

Small vessels surround the IVD during fetal development. These vessels begin to decrease in number during the first 2 years of life, and the remaining vessels that course within the subchondral bone to enter the deepest layers of the CEP are almost completely obliterated by 11 to 12 years of age, leaving the IVD as the largest avascular structure of the body. The first significant degenerative changes in the IVD appear shortly thereafter, as early as 11 to 16 years of age. This is when the last blood vessels leave the CEP. While the vessels decrease in number in the CEP, a rather dramatic decrease in the number of cells in the CEP, NP, and AF occurs (Liebscher et al., 2011). From this point on the NP and AF begin to show signs of degeneration (e.g., cell death, clefts, radial tears, degeneration of the extracellular matrix, and granular changes). Therefore even some teenagers may experience back pain as a result of IVD degeneration (Herzog, 1996). The increased cell death is replenished somewhat at this age by a marked increase in the proliferation of chondrocytes during this time (Boos et al., 2002).

The number of clefts and radial tears increases from 17 to 20 years of age. These changes are more prominent in the posterior than the anterior AF (Vernon-Roberts, Moore, & Fraser, 2007). In addition, the overall number of chondrocytes decreases as cell death, mucoid degeneration, and granular (scar tissue) changes begin to appear. These latter signs of degeneration increase throughout the second to the fourth decades of life. During the fifth and sixth decades of life the degenerative changes become the most severe; many clefts and tears filled with granular tissue become apparent throughout the IVD. Blood vessels (neovascularization) and nerve fibers able to conduct nociception have been found in many tears of elderly discs (Vernon-Roberts, Moore, & Fraser, 2007). Advanced tissue destruction and defects can be seen during this period of time. There is a high level of cell death (apoptosis) during these decades (Gruber & Hanley, 1998). Using a mouse model, Hutton and colleagues (1999) found that the rate of apoptosis in the CEP that occurs with aging and degeneration was also related to the rate of formation of osteophytes (spondylosis) along the superior and inferior margins of the vertebral bodies.

After 70 years of age the clefts and tears throughout the IVD have been filled with granular tissue, and the IVD assumes a homogeneous “burnt out” appearance, making the NP, AF, and CEP difficult to distinguish from one another (Boos et al., 2002).

There is no sex difference in the rate or severity of lumbar IVD degenerative changes, but the IVDs of whites show greater degenerative changes than the IVDs of individuals of African ethnicity. The L5-S1 IVDs show more degenerative changes than the other lumbar levels, particularly in individuals younger than 40 years of age (Siemionow et al., 2011).

Normal Aging of the Nucleus Pulposus and Anulus Fibrosus

The NP of fetal tissue contains many notochordal cells. The number of chondrocytes increases and the NP begins to assume slight mucoid characteristics during the first few months after birth. Subtle clefts develop in the NP during the next 2 years. The notochordal cells continue to die and the chondrocytes continue to increase in density between the ages of 3 and 10 years. There are virtually no notochordal cells left and there are significant clefts within the NP by 11 to 16 years of age. The number of clefts and radial fissures continues to increase until late in life (>70 years of age) when they have filled with granular (scar) tissue and are difficult to distinguish from the other tissue in the IVD. However, intranuclear clefts filled with fibrous (granular) tissue have been identified by means of T2-weighted MRI in patients just more than 30 years of age (Herzog, 1996). The outer lamellae of the AF are the last to show signs of degeneration, and these signs in the AF appear in the seventh decade of life (Boos et al., 2002).

Normal Aging of the Cartilaginous End Plate

The cartilaginous end plate (CEP) undergoes the earliest degenerative changes of the IVD. The CEP is well vascularized and slightly irregular in appearance during fetal development. Immediately after birth, the number of cells (primarily chondrocytes) increases dramatically and the cartilage takes on a disorganized appearance. During the next 16 years the number of blood vessels in the CEP steadily decreases, until there are no active vessels left by approximately 16 years of age (most are obliterated by 11 to 12 years of age) (Chandraraj, Briggs, & Opeskin, 1998; Boos et al., 2002). The decrease in active blood vessels is paralleled by the appearance of areas of obliterated vessels. These areas of obliterated vessels are already beginning to appear during the first 2 years of postnatal life. The number of regions of obliterated vessels dramatically increases until 16 years of age, when these regions are the most pronounced. The number of cells decreases significantly in the CEP until 16 years of age and then the numbers decline more gradually until the later decades of life (Liebscher et al., 2011). The number of PGs also decreases and the extracellular matrix becomes more disorganized as cell death increases (Antoniou et al., 1996; Roberts et al., 1996; Gruber & Hanley, 2002). Because the PGs dictate the solutes that are transported across the CEP and the rate of transport of these solutes, the decrease in the number of PGs may result in waste products accumulating in the IVD and nutrients being excluded from the IVD, both of which can lead to IVD degeneration.

Also between the ages of 11 and 16 years significant numbers of cracks appear in the CEP. The CEP cracks are accompanied by corresponding microfractures of the adjacent subchondral bone. These findings often are associated with new bone formation in the subchondral bone. The CEP cracks and the microfractures in the subchondral bone continue to increase during the second through the sixth decades, when the subchondral bone becomes sclerotic and regions of the CEP calcify. This leads to an increased vulnerability of the CEP to Schmorl’s node formation. In the seventh decade of life, the CEP stabilizes, and its appearance remains relatively the same throughout the remaining decades of life (Boos et al., 2002).

Normal Aging and Degeneration of the Bony End Plate

Even though the bony end plate is not a part of the IVD, the fates of the bony and cartilaginous end plates are so closely linked that a brief discussion of the normal aging and degeneration of the bony end plate is warranted. The relationship between degeneration of the bony end plate and formation of intravertebral herniations (Schmorl’s nodes) is also of clinical importance.

During the first few years of life, vessels within the vertebral body course into the cartilage growth cap (not the CEP, but subjacent to it) of the superior and inferior ends of the vertebral body. Vessels course within “vascular canals” within this cartilage. Each vascular canal contains several vessels that extend into the CEP. While the cartilage of the growth cap is replaced by bone, the vessels recede, leaving “cartilage nodes,” or areas of obliterated vessels, where the vascular canals once ended. These cartilage nodes fill with collagen from the CEP and NP and in some cases form what could be called “mini-Schmorl’s nodes.” Therefore the cartilage nodes represent weak spots in the vertebral bodies, and during the aging process they allow nuclear material to extrude through the thinning CEP and into and through the cartilage nodes; with further increase in IVD pressures, true Schmorl’s nodes can be formed (Chandraraj, Briggs, & Opeskin, 1998). In addition, multiple Schmorl’s nodes have been observed in individuals playing sports that create extensive axial loading (Hamanishi et al., 1994). Schmorl’s nodes are also sometimes seen in conjunction with typical disc protrusions, suggesting that axial loading is causing the NP to protrude in many directions (Chandraraj, Briggs, & Opeskin, 1998).

Unique Features of Intervertebral Disc Degeneration

Recall from previous chapters that degeneration of the IVDs is accompanied by nerve and vascular ingrowths into the disc. Schwann cells of the nerves innervating the outer layers of the AF appear to play a role in this ingrowth (Johnson et al., 2001). The increased innervation is attributable to free nerve endings containing increased amounts of substance P and calcitonin gene–related peptide (CGRP) (nociceptors). Therefore injured or degenerated discs are more pain sensitive than noninjured or nondegenerated IVDs (Coppes et al., 1997), and are particularly sensitive to inflammatory changes in the IVD (Ozawa et al., 2006). Also, remember from previous chapters that the IVDs thrive on reasonable motion within normal physiologic limits (Korecki, MacLean, & Iatridis, 2008). Consequently, frequent changes of posture improve and maintain the internal environment of the IVD, and an overly sedentary lifestyle is not beneficial for the IVD and the entire spine (Kraemer, 1995). Also, spending prolonged periods of time in postures that produce increases in IVD hydrostatic pressure, such as prolonged standing while carrying loads and prolonged sitting (again, an overly sedentary lifestyle), can affect PG and collagen synthesis, inhibit disc nutrition, and also lead to IVD degeneration (Kraemer, 1995; Hutton et al., 1998, 1999, 2002). In fact, hydrostatic pressure within the IVD has been found to have significant influences on IVD cell metabolism. Normal pressure in the IVD is approximately 3 atm (atmospheres). Pressures at this level were found in experiments (in vitro) conducted by Handa and colleagues (1997) to stimulate the synthesis of PGs and inhibit the production of matrix metalloproteinases (which degrade the PGs and collagen of the IVD) in both the NP and the inner AF. Pressures either greater than or less than 1 to 3 atm were found to increase the rate of disc degeneration (decreased production of PGs and increased production of matrix metalloproteinases). Lotz and colleagues (1998, 2000), using a mouse model, also found that prolonged graded compression resulted in graded IVD degeneration. They also noted that the IVDs showed signs of recuperation after having the increased pressures removed for 1 month. Other authors have found evidence that negative pressure, or distraction, may help the tissues of the IVD regenerate (e.g., increased hydration, increased numbers of cells that manufacture proteins, and up-regulation of gene expression for stimulating extracellular matrix production) (Guehring et al., 2006).

Proteoglycan Monomers and Proteoglycan Aggregates

PG monomers are complex macromolecules composed of many GAGs covalently bonded to a core protein of varying length. Three dimensionally, the side chains attached to the core protein form the shape of a “bottle brush” (see Fig. 14-6). The short branches of the bottle brush represent keratan sulfate, and the long ones represent chondroitin sulfate. PG monomers group together to form PG aggregates. The backbone of a PG aggregate is hyaluronic acid. Hyaluronic acid is a long coil-like chain composed of alternating molecules of glucuronic acid and glucosamine. The PG monomers are attached to hyaluronic acid by a link protein.

Glycosaminoglycans

GAGs refer to long-chain, unbranched carbohydrate polymers composed of repeating disaccharide units of glucosamine (or galactosamine) and glucuronic acid attached to a protein core. The hexosamine (glucosamine and galactosamine) usually is sulfated (see Table 14-4). However, an exception among the GAGs to this general pattern is hyaluronic acid, which is the longest GAG and has no sulfated hexosamines. Most of the carbohydrate molecules of GAG chains are negatively charged and repel each other. This negative charge attracts numerous Na⁺ ions, which are osmotically active. This causes a large amount of water to rush into the matrix and creates a swelling hydrostatic pressure. This hydrostatic pressure enables the matrix of cartilage and the IVD to withstand compressive forces.

GAGs are synthesized within the cells of the connective tissue in which they are found. For instance, the fibroblast is the primary cell type of connective tissue proper, and it produces and maintains the ground substance of this tissue, which primarily consists of GAGs. Chondroblasts are cells that produce the ground substance of cartilage, and osteoblasts produce the ground substance of bone. The GAGs for the entire IVD are probably primarily produced by the cells within the CEP. The time it takes to replace the PGs in the human IVD is considerable (approximately 3 years) and is longer than the replacement times found in other species (Table 14-5). Therefore much time is needed before complete repair of pathologic conditions or damage to the IVD can take place, and in some cases (especially if the CEP is damaged) repair may not be possible (Moore et al., 1996).

The principal GAGs of the extracellular matrix include the following:

These five types of GAGs differ in the following important ways: molecular weight, length of the chain, and type of disaccharide units. Table 14-4 summarizes the major characteristics of the principal GAGs. GAGs tend to exist in various configurations, which results in a variety of electrostatic charges among GAGs and allows them to participate in various degrees of interactions with adjoining chains. This variety of configurations and interactions of GAGs contributes to the formation of additional physical and chemical characteristics of the extracellular matrix.

Hyaluronic acid is by far the largest GAG, consisting of an estimated 2500 disaccharide units. Its molecular weight is approximately 106 Da. Hyaluronic acid is the major GAG of synovial fluid and many tissues (see Table 14-4). It is partially responsible for swelling within the extracellular matrix and also for attracting cells to the site of an injury. As mentioned previously, PG monomers also bind to hyaluronic acid to form PG aggregates.

Chondroitin 4-sulfate and chondroitin 6-sulfate consist of glucuronic acid and N-acetylgalactosamine. These two GAGs are similar in structure and function (see Table 14-4). Chondroitin 4-sulfate is the most abundant GAG found in the body and is present in immature cartilage. Chondroitin 6-sulfate is distributed in mature cartilage and other tissues. Decreased sulfation of the chondroitin sulfates has been related to IVD degeneration (Hutton et al., 1997).

Dermatan sulfate is the major GAG of skin, from which it derives its name. It is also distributed in tendons, ligaments, fibrocartilage, and other tissues. However, it is not found in the IVD or Z joints. Dermatan sulfate has a high affinity to associate closely with collagen type I fibers (see Tables 14-3 and 14-4).

Keratan sulfate is the shortest of the GAGs (see Table 14-4). It is found in skeletal tissue, as well as the cornea (keratan sulfate type I). Along with hyaluronic acid and chondroitin sulfate, keratan sulfate is a main contributor of cartilage PGs. It is also found in abundance in the NP of the IVD.

Heparan sulfate is associated with collagen type III reticular fibers, which are found in large amounts in basal laminae. Heparan sulfate is also distributed in the lungs, liver, and aorta. However, it is not found to any great extent in the Z joints or IVDs.

• Embryonic connective tissue

• Connective tissue proper

• Specialized connective tissue

Connective Tissue Proper

Connective tissue proper is tissue that, rather intuitively, seems to fall into the category of tissue that holds things together. It can be subdivided into two types: loose and dense (Mescher, 2010). This is based mostly on the relative amounts of fibers that can be found in the extracellular matrix. Further, dense connective tissue can be thought of as having two varieties, based mostly on the arrangement of the fibers in the extracellular matrix: irregular and regular.

Loose or areolar connective tissue is characterized by a large amount of fluid ground substance (Fig. 14-19). There are moderate amounts of cells and fibers that are loosely, or not closely, arranged in this ground substance. The cells are predominantly fibroblasts and macrophages, but other cell types common to connective tissue also can be found, especially lymphatic cells and mast cells. All three connective tissue fiber types (elastic, collagen [mostly type I], and reticular) are represented. In general, connective tissues do not have as rich of a blood supply as other, more metabolically active tissues (e.g., neural tissue), but for a connective tissue, loose connective tissue is quite vascular. The functional characteristics of this type of tissue are that it is rather flexible but not very strong. It is commonly found in the body. In the region of the back, it mainly supports epithelia (e.g., papillary layer of the dermis), surrounds bundles of muscle cells (perimysium), and ensheaths lymphatic and blood vessels. Loose connective tissue, along with adipose tissue (see the following), also forms the superficial fascia.

Dense irregular connective tissue has large numbers of fibers that are arranged in bundles that are oriented in various directions (see Fig. 14-19). These fibers are mostly collagen fibers composed of type I collagen. There are relatively few cells, which are mostly fibroblasts, and little ground substance, when compared with loose connective tissue. Therefore it is less flexible but much stronger than loose connective tissue. The three-dimensional arrangement of the fibers gives this tissue good strength in all directions. In the region of the back, dense irregular connective tissue may be found mostly in the reticular or deep layer of the dermis. Most of the supporting tissue of peripheral nerves (epineurium and perineurium) and muscles (epimysium and thicker types of perimysium) also consist of dense irregular connective tissue. The fibrous layers of the periosteum and perichondrium are also considered to be this type of tissue.

The components of dense regular connective tissue are similar to those of dense irregular connective tissue, but their arrangement is different. In this case, the bundles of fibers are arranged linearly, with rows of cells, mostly fibroblasts, and a minimal amount of ground substance located between the bundles. This arrangement gives a tremendous amount of resistance to traction stresses in one direction (parallel to the fibers). In the back region, three main types of structures are composed of this tissue: tendons, ligaments, and deep fascia.

Tendons, the structures that connect muscles to bone, are composed of closely packed bundles of collagen fibers (see Fig. 14-23). These fibers are almost exclusively type I collagen. Between the bundles of fibers are rows of tendinocytes, which resemble fibroblasts. The bundles of collagen fibers are grouped together into fascicles, which are continuous with the corresponding fascicles of the muscle to which they attach (see the following). Each fascicle is invested or surrounded by a thin layer of loose connective tissue called the endotendineum (see Fig. 14-21). The endotendineum contains blood vessels and nerves. Surrounding the entire tendon is a thin layer of dense irregular connective tissue called the epitendineum.The endotendineum septa are continuous with the epitendineum. Recent advances are leading to a more integrated understanding of tendons and their relationship with fascia (see following section). This has led to a better appreciation of their function (Benjamin, Kaiser, & Milz, 2008).

Ligaments connect bones or cartilages and serve to support and strengthen joints. Like tendons, the bundles of fibers are linearly arranged in ligaments, although not quite as uniformly (Ross et al., 2003). Also, unlike tendons, there is no fascicular arrangement of the bundles of fibers, making ligaments less vascular than tendons. In most ligaments of the body, the fibers are predominantly type I collagen fibers, giving a great amount of tensile strength, but no elasticity (see Fig. 14-19). Because of the high amount of collagen, these ligaments appear white to the unaided eye, and sometimes this dense regular collagenous tissue is called white connective tissue. One exception to this is the ligamentum flavum. It is composed of dense regular connective tissue, but most of the fibers in its extracellular matrix are elastic fibers, not collagen fibers. Under the microscope, longitudinal sections of these bundles of elastic fibers have a distinctive wavy appearance (see Fig. 14-19). This type of fiber gives the ligamentum flavum not only good tensile strength but also elasticity. Masses of elastic fibers have a distinct yellow-orange color when viewed by the unaided eye. Therefore dense regular elastic connective tissue sometimes is known as yellow connective tissue. This coloration is also responsible for the name flaval ligament (i.e., ligamentum flavum), because flavus means yellow in Latin.

The site where a tendon or ligament attaches to a bone is called an enthesis. Most authors recognize at least two types of enthesis: fibrous and fibrocartilaginous (Benjamin et al., 2006). In a fibrous enthesis, the dense regular connective tissue of the tendon or ligament attaches either directly to the bone or indirectly to it via the periosteum. The fibrocartilaginous enthesis is more common, especially for tendons (Benjamin, Evans, & Copp, 1986). Four zones are recognized as comprising a fibrocartilaginous enthesis. These include (from superficial to deep) (1) tendon/ligament, (2) fibrocartilage, (3) calcified fibrocartilage, and (4) bone. Recently the concept of an “enthesis organ” has been proposed (Benjamin et al., 2006). This term has been used to describe the collection of related tissues at or near an enthesis, which serve a common function of stress dissipation. The concept of the enthesis organ can have major implications for the clinician because this concept helps to explain patterns of injury and the diffuse nature of signs and symptoms associated with particular types of enthesopathies (i.e., enthesis injuries).

Bone

Bone is a specialized connective tissue in which the extracellular matrix is mineralized mostly by calcium phosphate in the form of hydroxyapatite crystals. This makes bone tissue hard, such that it forms the rigid support of the body as the skeleton. Bone also plays a vital role in the regulation of blood calcium levels by acting as a reservoir for both calcium and phosphate. Therefore unlike the dried skeletons that are studied in school, bone is a living, highly vascular, constantly changing tissue.

The organic portions of the extracellular matrix are composed of fibers and ground substance. The vast majority of the fibers are type I collagen fibers. These comprise the main structural component of the extracellular matrix of bone (Ross et al., 2003). The ground substance is composed of mostly GAGs that are similar to those of other connective tissues (see the preceding sections). Several special glycoproteins found only in the ground substance of bone tissue appear to be involved with the promotion of mineralization of the matrix. During the mineralization process, the mineral salts become associated not only with the ground substance but also with the collagen fibers.

Within the extracellular matrix are physical holes known as lacunae (singular, lacuna). Each contains a cell known as an osteocyte. Because there is little to no diffusion through the hardened extracellular matrix, there are tunnels in the matrix known as canaliculi, which contain cytoplasmic processes of osteocytes. At the point where the process of one osteocyte encounters the process of a different osteocyte in the canaliculus is a gap junction. This allows communication and diffusion of materials between the osteocytes.

Three other types of cells are associated with bone tissue:

Osteoprogenitor cells are found primarily on the outer and inner surfaces of bone tissue. They are pluripotential cells of mesenchymal origin that undergo a continual process of mitosis. They mostly give rise to osteoblasts, although during bone repair (e.g., after fracture) they may develop into other types of cells involved in that process.

Osteoblasts are the differentiated bone cells that give rise to bone matrix. They secrete both collagen and ground substance in an unmineralized form known as osteoid. This addition of new osteoid on the existing surface of bone tissue is known as appositional growth. Active osteoblasts exhibit the same cytoplasmic architecture as other cells that secrete large amounts of protein (e.g., abundant rough endoplasmic reticulum and a well-developed Golgi apparatus). In actively growing bones, osteoblasts are found alongside each other exclusively on the surfaces of bone tissue in a way reminiscent of simple cuboidal epithelium, but without any basal lamina. Although osteoblasts appear to be polar in nature and secrete osteoid on only one side, occasionally an osteoblast may become completely surrounded by osteoid. When this happens, a new lacuna is formed, and the cell becomes known as an osteocyte.

Osteoclasts are the bone cells responsible for resorption of bone matrix. They are large, multinucleated cells that are in physical contact with the surface of bone tissue. At this contact point the cytoplasm of these cells forms many folds that look like microvilli, giving it the appearance of a ruffled border. Lysosomal hydrolases are released from this ruffled border that digest the bone matrix outside the cell, creating shallow indentations in the bone matrix known as resorption bays or Howship’s lacunae. Osteoclasts appear to endocytose the digested bone matrix, because large numbers of coated vesicles can be found in the region of the ruffled border. Osteoclasts, unlike osteoprogenitor cells, appear to originate from the same mononuclear hemopoietic progenitor cells that differentiate into monocyte lineages. This makes osteoclasts closely related to macrophages, in both origin and function.

There are two main arrangements of bone tissue seen in mature bone (e.g., the vertebrae) (Fig. 14-22). A dense layer of compact bone forms the outer portion of bones. Spongy, or cancellous, bone, which consists of a network of bony trabeculae (from the Latin word for beam) and spicules, forms the interior of the vertebrae. The spaces between the trabeculae are known as the marrow cavities and are occupied by blood vessels and bone marrow, which is the main hemopoietic tissue of the body.

Compact bone consists of collections of cylindrical units of concentric lamellae (singular, lamella) or layers of mineralized extracellular matrix surrounding a centrally located canal. These units are known as osteons or haversian systems. The collagen fibers within a single lamella are arranged parallel with each other, but in different directions when compared with adjacent lamellae. This arrangement, reminiscent of plywood, gives compact bone tissue great strength. The centrally located canal is known as the osteonal or haversian canal and contains blood vessels, nerves, and some loose connective tissue. The haversian canals usually run parallel to the long axis of the bone. Lacunae, containing osteocytes, are located mostly between the concentric lamellae, although some may be located within the lamellae. Canaliculi, containing osteocyte processes, generally are arranged in a radial pattern with respect to the haversian canals. Perforating or Volkmann’s canals are channels carrying blood vessels and nerves that travel from the superficial surface of the bone to the marrow cavities. They usually run perpendicular or oblique to the haversian canals, such that the Volkmann’s canals also connect haversian canals with each other.

Spongy bone is similar in structure to compact bone, except that the matrix is arranged in trabeculae and spicules. If the trabeculae are relatively thick, they may contain true osteons; otherwise, the trabeculae are composed of irregularly arranged lamellae of matrix and lacunae. There are numerous interconnecting marrow cavities of various sizes between the portions of bony matrix. This honeycomb arrangement of the mineralized matrix gives cancellous bone great strength with relatively little weight.

The bones of the skeleton can be called organs because they are composed of several tissues. Not only are they composed of bone tissue, but also they have other connective tissues (e.g., hemopoietic and adipose tissues, blood vessels, nerves) and usually some sort of specialized articular regions (e.g., in the vertebrae; see the preceding discussions of Z joints and IVDs). A layer of dense, irregular connective tissue called periosteum covers the outer surface of bones, except where there are specializations for the formation of a joint. The periosteum has a more fibrous outer layer with fibroblasts and type I collagen fibers. The inner layer is more cellular and consists mostly of osteoprogenitor cells. There are special bundles of periosteal collagen fibers called Sharpey’s fibers that penetrate into the bone matrix and attach the periosteum to the bone. Periosteum contains a rich vascular supply and network of nerves. Endosteum is the connective tissue layer that lines the inner surface of bones and surrounds the marrow cavity. It is thinner than the periosteum, being mostly a single layer of osteoprogenitor cells with a minimal amount of extracellular matrix.

Neurons

The human nervous system contains more than 10 billion neurons (Ross et al., 2003). Functionally, there are three general categories of neurons: afferent, efferent, and interneurons. Afferent neurons carry information, generally sensory in nature, from the periphery into the CNS. Efferent neurons carry information, much of which is motor, from the CNS to targets in the periphery. Interneurons, which make up the vast majority of the neurons in the nervous system, communicate between neurons within the CNS.

Each neuron consists of a cell body and processes, known as axons and dendrites (Fig. 14-24). The cell body (soma or perikaryon) contains the nucleus of the cell. Unfortunately, a couple of terms can be confusing. The term nucleus not only can refer to the organelle of the neuron that contains the genetic material, but also can be used to denote a collection of nerve cell bodies within the CNS. The term neuron not only is used for the conductive cells of the nervous system, but also is sometimes used to refer only to the nerve cell body. This latter definition of the term neuron is used more often when referring to the nerve cell bodies that are found in the nuclei of the CNS or in peripheral ganglia. Besides the nucleus of the cell, the cell body contains the usual cytoplasmic organelles present that maintain the cell. Prominent in the cytoplasm are stacks of rough endoplasmic reticulum or polyribosomes called Nissl substance or bodies. These are necessary because neurons synthesize a large amount of proteins. Mitochondria also are represented in large numbers because of the high metabolic activity associated with neurons.

Besides a cell body, each neuron has a variable number of processes. Each neuron has a single axon that carries impulses away from the soma and forms a synapse (or synapses) where it contacts another neuron or other effector target. Most axons ramify distally such that a typical neuron in the CNS forms more than 1000 synapses (Kandel & Siegelbaum, 2000). The specific portion of the axon that helps form a synapse is known as the axon terminal or terminal bouton. The region of the cell body from which the axon arises is known as the axon hillock. There is a characteristic lack of Nissl substance in this region. Just distal to the axon hillock is the initial segment of the axon. It is in this location that action potentials are generated. Most axons are relatively long, as compared with dendrites, and many are myelinated. Neurons almost always have dendrites that carry impulses toward the soma. Typically dendrites are short, thicker in diameter than axons, and unmyelinated. In most neurons the dendrites ramify extensively into what is known as the dendritic tree. Neurons may be classified by the number of processes they have. Multipolar neurons have one axon and two or more dendrites. Motor neurons and interneurons typically have this morphology. Bipolar neurons have one axon and one dendrite. They are only found associated with the neural circuitry of the special senses. Pseudounipolar or unipolar neurons have a single process that is axonal in structure. Actually, during development these cells had a separate dendrite and axon that fused together to make a single process attaching to the soma. This single process splits into a central process that enters the CNS and a peripheral process that terminates peripherally as a sensory receptor. Only primary somatosensory afferent neurons have this arrangement.

Because most synthetic activity is restricted to the soma of the neurons, it is necessary to have an axonal transport system to move materials along the processes of the neuron, including dendrites. This transport system uses mostly microtubules and intermediate filaments to move materials. Axonal transport is a bidirectional system. Anterograde transport carries material from the soma to the periphery of the cell, whereas retrograde transport moves molecules from the periphery to the cell body. It has been shown that various types of materials in the cell are transported at different speeds such that both slow and fast axonal transport systems are recognized in neurons.

A synapse is the site of functional apposition between neurons, at which an impulse is transmitted from one neuron (the presynaptic neuron) to another (the postsynaptic neuron). Synapses are also found between neurons and their nonneural effector (target) cells (e.g., muscle or gland cells). Synapses may be formed between various parts of neurons. Most commonly they are axodendritic, in which a presynaptic axon forms a synapse with a postsynaptic dendrite. Many times in the CNS, the postsynaptic dendrite has a special structure for the synapse known as a dendritic spine that may help modify synaptic activity. Synapses may also form between axons and cell bodies of neurons (axosomatic) and between axons of two neurons (axoaxonic). In vertebrates, almost all synapses are chemical synapses in which the conduction of impulses from one neuron to the next is achieved by the release of a chemical neurotransmitter (e.g., acetylcholine, norepinephrine, and glycine) by the presynaptic terminal. The neurotransmitter diffuses across the synaptic cleft, which is the 20- to 30-nm space that separates the two neurons involved in the synapse. The neurotransmitter then may either excite (depolarize) or inhibit (hyperpolarize) the cell membrane of the postsynaptic neuron. This is achieved by interaction of the neurotransmitter with ligand-gated ion channels that are located in the postsynaptic membrane. These ion channels appear to be organized by an electron-dense structure known as the postsynaptic density. There are a few electrical synapses known as nexuses that can be found in certain places of the vertebrate CNS. These allow action potentials to spread directly from one neuron to the next and are structurally and functionally identical to the gap junctions that occur between cardiac muscle cells and between smooth muscle cells.

A typical neuron in the CNS is postsynaptic to or receives thousands of synapses (Kandel & Siegelbaum, 2000). Ultimately, the ability of an action potential to be generated in the postsynaptic neuron depends on the summation of all of the synaptic activity on the neuron. If the synaptic activity sufficiently depolarizes the cell membrane to reach threshold, an action potential is generated in the initial segment of the axon and carried by the axon to the synapse(s) for which it is presynaptic. If threshold is not reached, the cell does not generate an action potential, and the impulse from the presynaptic neurons is not passed along the neural circuit.

Neuroglia

There are approximately 10 times more neuroglia or glial cells than neurons in the mammalian nervous system (Mescher, 2010). These supporting cells surround the nerve cell bodies and processes and furnish the microenvironment for the neurons. Sometimes only the supporting cells of the CNS are termed neuroglia, whereas the ones in the PNS are referred to only as supporting cells or peripheral neuroglia (Ross et al., 2003). The various types of neuroglia include the following:

Schwann cells are associated with axons in the PNS. These axons are either myelinated or unmyelinated. If the axon is unmyelinated, it is embedded within a simple cleft in the Schwann cell (Ross et al., 2003). This helps maintain the microenvironment of the unmyelinated axon. Unlike with myelinated axons, a single Schwann cell may be associated with multiple unmyelinated axons. A lipid-rich layer known as the myelin sheath surrounds myelinated axons and acts as an insulator (or more correctly, a capacitor) for the axon, allowing saltatory proliferation of the action potentials carried by the axon. The myelin sheath is composed of layers of the plasmalemma of the Schwann cells. Each Schwann cell wraps tightly around a single axon multiple times in a spiral fashion reminiscent of a cinnamon roll. The Schwann cell cytoplasm of each layer is removed such that the layers of the Schwann cell membrane fuse with each other to form the lipoprotein complex known as myelin. A thin cytoplasmic rim remains and surrounds the myelin. This rim, which contains the organelles of the Schwann cell, including its nucleus, is known as the neurilemma. Islands of cytoplasm found in the myelin sheath are known as clefts of Schmidt-Lanterman and appear to be necessary for metabolic maintenance of the myelin. The myelin sheath is interrupted at intervals by the nodes of Ranvier. These gaps between adjacent Schwann cells are necessary for saltatory conduction of action potentials. Saltatory conduction causes the axon cell membrane in the gap between two Schwann cells to depolarize; the depolarization then “skips” from one gap to the next along the axon. Saltatory conduction dramatically increases the conduction velocity of axons.

Oligodendrocytes or oligodendroglia are associated with axons in the CNS. They provide the myelination for these axons in a way similar to that of Schwann cells in the PNS. Unlike Schwann cells, which surround a single axon, oligodendrocytes surround more than one axon. Oligodendrocytes have several dendritelike processes, hence the name of the cell, each of which surrounds an axon. There are other biochemical differences in the myelination of CNS versus PNS axons that may be involved in the lack of regenerative ability of CNS axons.

Astrocytes are support cells of the CNS. These are by far the most numerous type of glial cell, and therefore the most numerous type of cell in the nervous system. Each has a cell body with numerous processes giving it a starlike shape, hence the name. Cells with fewer, longer processes are known as fibrous astrocytes and are located in the white matter. Cells with more numerous, shorter processes are called protoplasmic astrocytes and are found in the gray matter. Astrocytes completely surround the neurons of the CNS, except where they are myelinated by the oligodendrocytes. Astrocytes have a unique type of intermediate filament made of glial fibrillar acidic protein that helps these cells provide strong structural support to the neurons. Astrocytes also help relate neurons to capillaries. In fact, some astrocytes have processes with expanded end-feet that attach to capillaries. These appear to have a role in maintaining the blood-brain barrier. Astrocytes appear to help regulate the movement of metabolites and wastes into and out of neurons along with controlling the ionic concentration of the extracellular compartment. Therefore astrocytes appear to play a major role in maintaining the microenvironment of the CNS neurons and their synapses.

Satellite cells surround the soma of neurons in peripheral ganglia. Ganglia or peripheral ganglia are collections of nerve cell bodies in the PNS. Satellite cells appear to have a similar function to Schwann cells associated with unmyelinated axons in the PNS or astrocytes in the CNS. They help establish and maintain the microenvironment of the cell bodies of neurons in the ganglia.

Ependymal cells form the simple cuboidal to columnar epithelial lining of the ventricles of the brain and the central canal of the spinal cord, which are the remnants of the lumen of the neural tube. The basal surfaces of the ependymal cells interdigitate with astrocyte processes. There is no basal lamina associated with this epithelium. The apical surfaces of ependymal cells have cilia that may help move cerebrospinal fluid. Microvilli also can be found on the apical surface of these cells. These may be involved with absorption of cerebrospinal fluid.

Microglia are elongated cells that are relatively small and possess several irregular processes. They are actively phagocytic in regions of injury or disease. They represent the mononuclear phagocytic system in the CNS. As such they are derived from the bone marrow and migrate to the CNS by way of blood vessels.

Organization of the Central Nervous System

As stated, the CNS consists of the brain and spinal cord. All of the cells of the CNS, with the exception of microglia, are derived from the neural tube (see Chapter 12). When sectioned and viewed with the unaided eye, there are regions that look lighter in color (white matter) and darker in color (gray matter). White matter consists mostly of myelinated and unmyelinated nerve fibers along with their associated glial cells. In the CNS, a nerve fiber is an axon with its associated oligodendrocytes. The presence of large amounts of the fatty substance myelin is responsible for the lighter color. There are no neuron cell bodies in white matter. Gray matter is composed of nerve cell bodies, dendrites, axons (myelinated and unmyelinated), and associated glial cells. Sometimes the term neuropil is used to describe the mass of neuronal processes in the gray matter. Synapses are located in the regions of gray matter. The relative lack of myelin in these regions is responsible for their darker color. In much of the brain, the gray matter is located peripherally, whereas the white matter is more internal, although the regions of gray and white matter are not separated as simply in the brain stem. Discrete groups of functionally related nerve cell bodies in the CNS gray matter are called nuclei.

The relationship of the gray and white matter in the spinal cord is reversed when compared with that of most of the brain. The gray matter of the spinal cord is internal and forms the general shape of a capital H. The ventral cornua or horns contain neurons that are involved in motor function. Very large, multipolar neurons that innervate skeletal muscles are located here. These multipolar neurons are sometimes called lower motor neurons, and the axons of these neurons form the ventral roots of the spinal nerves. The dorsal horns have neurons, most of which are relatively smaller in size, that are concerned with sensory functions. Sensory input into the dorsal horns enters via the dorsal roots of the spinal nerves. Several discrete nuclei are recognized in the gray matter of the spinal cord. In the center of the spinal cord is the central canal, which is the remnant of the caudal portion of the neural tube lumen and is lined with ependymal cells.

The white matter surrounds the gray matter of the spinal cord. This tissue consists of various functionally related columns of nerve fibers called tracts or fasciculi that mostly run in a vertical fashion to carry information to and from the brain. Other groups of fibers called commissures also connect structures on opposite sides of the spinal cord. Many other intersegmental fibers can be found in the white matter of the spinal cord.

Few connective tissues are found within the brain and spinal cord, so they are soft and watery in nature; however, three layers of connective tissue, known as meninges (singular, meninx), surround the CNS. These layers are of mesenchymal origin. They are, from superficial to deep, dura mater, arachnoid, and pia mater. The dura mater or pachymeninx is the thickest and toughest of the meninges. It consists of dense, irregular collagenous connective tissue. Unlike around the brain, where it fuses with the inner periosteum of the skull, the dura mater surrounding the spinal cord is separated from the vertebrae by a fat-filled epidural space. The dura mater has a rich blood supply and is innervated.

The other two layers of the meninges are thin compared with the dura mater and are sometimes collectively known as the leptomeninges. The arachnoid is a thin avascular layer of connective tissue that is loosely adherent to the dura and separated from the dura mater by a potential space known as the subdural space. The arachnoid also has delicate trabeculae composed of loose connective tissue that connect it with the pia mater. These trabeculae give the arachnoid a spiderweb appearance, hence the name. The regions between the trabeculae are collectively called the subarachnoid space. The subarachnoid space is filled with cerebrospinal fluid. The pia mater is a very thin layer usually consisting of a single layer (or in some places several layers) of cells that is intimately attached to the entire surface of the CNS. It also surrounds the perivascular connective tissue of the arteries and veins, but not capillaries, of the brain and spinal cord.

The capillaries of the CNS are less permeable to certain substances than in other parts of the body. This decreased permeability of these capillaries is termed the blood-brain barrier. It is mostly the result of occluding junctions between the endothelial cells, making these continuous-type capillaries. These occluding junctions are morphologically similar to tight junctions of other types of epithelia. The end-feet of astrocytes that are associated with these capillaries also seem to be involved in this blood-brain barrier, especially in maintaining water homeostasis in the CNS (Ross et al., 2003).

Organization of the Peripheral Nervous System

The main components of the PNS are nerves, ganglia, and nerve endings. Other than the nerve endings described previously (i.e., muscle spindles and Golgi tendon organs), the structure of the other types of nerve endings, which are mostly cutaneous in nature, is beyond the scope of this discussion. See Peripheral Receptors in Chapter 9 for a discussion of this topic.

Nerves, or peripheral nerves, are bundles of nerve fibers, usually both myelinated and unmyelinated, held together by connective tissue. In the PNS, a nerve fiber is essentially an axon and the surrounding Schwann cells. In the spinal nerves, the cell bodies for the motor nerve fibers are located in the anterior horn of the spinal cord. The cell bodies for the sensory nerve fibers are located in the dorsal root ganglion (see the following).

Surrounding each Schwann cell–ensheathed axon is a thin layer of reticular fibers called the endoneurium. These fibers appear to be produced by the Schwann cells, because there is a lack of fibroblasts in the vicinity. The fibers run both parallel to and around the axons, functionally binding them into fascicles. Around each fascicle of axons is the perineurium. It is made up of one or more layers of flattened epithelial-like cells. When there is more than one layer of perineurial cells (e.g., in the larger-caliber nerve fascicles) these cells appear to produce collagen fibers. They may even be contractile, given the large amount of actin found in their cytoplasm (Ross et al., 2003). Tight junctions connect the perineurial cells. Therefore perineurium acts as a metabolic diffusion barrier for the nerve fibers and establishes a blood-nerve barrier similar to the blood-brain barrier of the CNS. This protective function of the perineurium seems important to the normal functioning of peripheral nerves. In fact, there is a dearth of classic connective tissue cells, including most immune system cells, within peripheral nerves. About the only cells other than Schwann cells that can be found within a peripheral nerve are the occasional fibroblast and some mast cells. Surrounding the entire nerve is a relatively thick, dense irregular collagenous connective tissue layer known as the epineurium. In larger nerves adipose tissue may be associated with the epineurium. Blood vessels (vasa nervorum) and nerves (nervi nervorum) supplying the nerve penetrate into the epineurium and travel in the perineurium. The tissue at the level of the endoneurium is poorly vascularized, and metabolic exchange must occur through diffusion from the perineurium. In the region of the intervertebral foramen, the epineurium of the spinal nerves becomes continuous with the dural root sleeve surrounding the spinal nerve roots (see Chapter 3).

Ganglia are collections of nerve cell bodies in the PNS that have a connective tissue framework and capsule for support. There are two varieties of ganglia. The first is sensory ganglia. The neuronal cells in these ganglia are pseudounipolar. Each cell body is surrounded by cuboidal-shaped satellite cells. The fibers associated with sensory ganglia are the peripheral and central processes of the pseudounipolar neurons. These fibers only travel through the ganglion and do not synapse. Dorsal root ganglia are the example of this type of ganglion in the region of the back. The second type of ganglion is the autonomic ganglion. The cell bodies of the multipolar postganglionic autonomic neurons reside in these ganglia. Usually there is a layer of relatively flattened satellite cells surrounding the cell bodies of these neurons. Unlike the sensory ganglia, in which no synapses occur, there is an abundance of synapses in autonomic ganglia. These are where the axons of preganglionic autonomic neurons synapse with the dendrites of the postganglionic autonomic neurons. The ganglia of the sympathetic gangliated chains are examples of this type of ganglion in the region of the back.