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Chapter 8. Bone

 

 

Bone: Introduction

As the main constituent of the adult skeleton, bone tissue supports fleshy structures, protects vital organs such as those in the cranial and thoracic cavities, and harbors the bone marrow, where blood cells are formed. Bone also serves as a reservoir of calcium, phosphate, and other ions that can be released or stored in a controlled fashion to maintain constant concentrations of these important ions in body fluids.

In addition, bones form a system of levers that multiply the forces generated during skeletal muscle contraction and transform them into bodily movements. This mineralized tissue therefore confers mechanical and metabolic functions to the skeleton.

Bone is a specialized connective tissue composed of calcified intercellular material, the bone matrix, and three cell types:

§         Osteocytes (Gr. osteon, bone + kytos, cell), which are found in cavities (lacunae) between layers (lamellae) of bone matrix (Figure 8–1)

§         Osteoblasts (osteon + Gr. blastos, germ), which synthesize the organic components of the matrix

§         Osteoclasts (osteon + Gr. klastos, broken), which are multi-nucleated giant cells involved in the resorption and remodeling of bone tissue.

 

 

 

 

 

Because metabolites are unable to diffuse through the calcified matrix of bone, the exchanges between osteocytes and blood capillaries depend on communication through the canaliculi (L. canalis, canal), which are very thin, cylindrical spaces that perforate the matrix (Figure 8–1).

All bones are lined on both internal and external surfaces by layers of connective tissue containing osteogenic cells—endosteum on the internal surface and periosteum on the external surface.

Because of its hardness, bone cannot be sectioned with the microtome, and special steps must be taken to study it histologically. A common technique that permits the observation of the cells and the organic part of the matrix is based on the decalcification of bone preserved by standard fixatives. The mineral is removed by immersion in a solution containing a calcium-chelating substance such as ethylenediaminetetraacetic acid (EDTA). The decalcified tissue is then embedded, sectioned, and stained as usual.

 

 

Bone Cells

Osteoblasts

Osteoblasts are responsible for the synthesis of the organic components of bone matrix, consisting of type I collagen fibers, proteoglycans, and several glycoproteins including osteonectin. Deposition of the inorganic components of bone also depends on viable osteoblasts. Osteoblasts are located exclusively at the surfaces of bone matrix, usually side by side in a layer somewhat resembling a simple epithelium (Figure 8–2). When they are actively engaged in matrix synthesis, osteoblasts have a cuboidal to columnar shape and basophilic cytoplasm. When their synthesizing activity declines, they flatten and cytoplasmic basophilia is reduced. Osteoblast activity is stimulated by parathyroid hormone (PTH).

 

 

 

 

 

During matrix synthesis, osteoblasts have the ultrastructure of cells actively synthesizing proteins for secretion. Osteoblasts are polarized cells: matrix components are secreted at the cell surface in contact with older bone matrix, producing a layer of new (but not yet calcified) material called osteoid between the osteoblast layer and the bone formed earlier (Figure 8–2). This process of bone appositional growth is completed by subsequent deposition of calcium salts into the newly formed matrix.

Calcification of the matrix is not completely understood, but basic aspects of the process are shown in Figure 8–3. Prominent among the noncollagen proteins secreted by osteoblasts is the small, vitamin K-dependent polypeptide osteocalcin, which together with various glycoproteins binds Ca2+ ions and raises their concentration locally. Osteoblasts also release membrane-enclosed vesicles rich in alkaline phosphatase and other enzymes whose activity raises the local concentration of PO4- ions. With high concentrations of both ions, these matrix vesicles serve as foci for the formation of hydroxyapatite [Ca10(PO4)6(OH)2] crystals, the first visible step in calcification. These crystals grow rapidly by accretion of more mineral and eventually form a confluent mass of calcified material embedding the collagen fibers and proteoglycans.

 

 

 

 

Osteocytes

Individual osteoblasts are gradually surrounded by their own secretion and become osteocytes enclosed singly within spaces called lacunae. In the transition from osteoblasts to osteocytes the cells extend many long cytoplasmic processes, which also become surrounded by calcifying matrix. An osteocyte and its processes occupy each lacuna and the canaliculi radiating from it (Figures 8–4 and 8–1).

 

 

 

 

Processes of adjacent cells make contact via gap junctions, and molecules are passed via these structures from cell to cell. The exchange via gap junctions can provide nourishment for a chain of about ten cells. Some molecular exchange between osteocytes and blood vessels also takes place through the small amount of extracellular fluid located between osteocytes and the bone matrix.

When compared with osteoblasts, the flat, almond-shaped osteocytes exhibit a significantly reduced RER and Golgi apparatus and more condensed nuclear chromatin (Figure 8–4a). These cells are involved in maintaining the bony matrix and their death is followed by resorption of this matrix.

 

 

MEDICAL APPLICATION

The fluorescent antibiotic tetracycline interacts with great affinity with recently deposited mineralized bone matrix. Based on this interaction, a method was developed to measure the rate of bone apposition—an important parameter in the study of bone growth and the diagnosis of bone growth diseases. Tetracycline is administered twice to patients, with an interval of 5 days between injections. A bone biopsy is then performed, and the sections are studied by means of fluorescence microscopy. The distance between the two fluorescent layers is proportional to the rate of bone apposition. This procedure is of diagnostic importance in such diseases as osteomalacia, in which mineralization is impaired, and osteitis fibrosa cystica, in which increased osteoclast activity results in removal of bone matrix and fibrous degeneration.

 

 

Osteoclasts

Osteoclasts are very large, motile cells with multiple nuclei (Figure 8–5). The large size and multinucleated condition of osteoclasts is due to their origin from the fusion of bone marrow-derived cells. In areas of bone undergoing resorption, osteoclasts lie within enzymatically etched depressions or crypts in the matrix known as resorption bays (formerly called Howship lacunae).

 

 

 

 

In active osteoclasts, the surface against the bone matrix is folded into irregular projections, which form a ruffled border. Formation of the ruffled borders is related to the activity of osteoclasts. Surrounding the ruffled border is a clear cytoplasmic zone rich in actin filaments which is the site of adhesion to the bone matrix. This circumferential adhesion zone creates a microenvironment between the osteoclast and the matrix in which bone resorption occurs (Figure 8–5).

Into this subcellular pocket the osteoclast secretes collagenase and other enzymes and pumps protons, forming an acidic environment locally for dissolving hydroxyapatite and promoting the localized digestion of collagen. Osteoclast activity is controlled by local signaling factors and hormones. Osteoclasts have receptors for calcitonin, a thyroid hormone, but not for parathyroid hormone. Osteoblasts activated by PTH produce a cytokine called osteoclast stimulating factor. Thus, activity of these two cells is coordinated and both are essential in bone remodeling.

 

 

Bone Matrix

Inorganic material represents about 50% of the dry weight of bone matrix. Hydroxyapatite is most abundant, but bicarbonate, citrate, magnesium, potassium, and sodium are also found. Significant quantities of amorphous (noncrystalline) CaPO4 are also present. The surface ions of hydroxyapatite are hydrated and a layer of water and ions forms around this crystal. This layer, the hydration shell, facilitates the exchange of ions between the crystal and the body fluids.

 

 

MEDICAL APPLICATION

In the genetic disease osteopetrosis, which is characterized by dense, heavy bones ("marble bones"), the osteoclasts lack ruffled borders, and bone resorption is defective.

The organic matter embedded in the calcified matrix is type I collagen and ground substance, which contains proteoglycan aggregates and several specific multiadhesive glycoproteins, including osteonectin. Calcium-binding glycoproteins, notably osteocalcin, and the phosphatases released in matrix vesicles by osteoblasts promote calcification of the matrix. Other tissues containing type I collagen do not contain these glycoproteins or matrix vesicles and are not normally calcified. Because of its high collagen content, decalcified bone matrix is usually acidophilic.

The association of minerals with collagen fibers is responsible for the hardness and resistance of bone tissue. After a bone is decalcified, its shape is preserved, but it becomes as flexible as a tendon. Removal of the organic part of the matrix—which is mainly collagenous—also leaves the bone with its original shape; however, it becomes fragile, breaking and crumbling easily when handled.

 

 

Periosteum & Endosteum

External and internal surfaces of bone are covered by layers of bone-forming cells and vascularized connective tissue called periosteum and endosteum.

The periosteum consists of a dense fibrous outer layer of collagen bundles and fibroblasts (Figures 8–1 and 8–6). Bundles of periosteal collagen fibers, called perforating(or Sharpey's) fibers, penetrate the bone matrix, binding the periosteum to bone. The innermost cellular layer of the periosteum contains mesenchymal stem cells called osteoprogenitor cells, with the potential to divide by mitosis and differentiate into osteoblasts. Osteoprogenitor cells play a prominent role in bone growth and repair.

 

 

 

 

The large internal marrow cavities of bone are lined by endosteum (Figures 8–1 and 8-6). Endosteum is a single very thin layer of connective tissue, containing flattened osteoprogenitor cells and osteoblasts, which covers the small spicules or trabeculae of bone that project into these cavities. The endosteum is therefore considerably thinner than the periosteum.

The principal functions of periosteum and endosteum are nutrition of osseous tissue and provision of a continuous supply of new osteoblasts for repair or growth of bone.

 

 

Types of Bone

Gross observation of bone in cross section shows dense areas generally without cavities—corresponding to compact bone—and areas with numerous interconnecting cavities—corresponding to cancellous (spongy) bone (Figure 8–7). Under the microscope, however, both compact bone and the trabeculae separating the cavities of cancellous bone have the same basic histologic structure.

 

 

 

 

 

In long bones, the bulbous ends—called epiphyses (Gr. epiphysis, an excrescence)—are composed of spongy bone covered by a thin layer of compact bone. The cylindrical part—the diaphysis (Gr. diaphysis, a growing between)—is almost totally composed of compact bone, with a thin component of spongy bone on its inner surface around the bone marrow cavity. Short bones usually have a core of spongy bone surrounded completely by compact bone. The flat bones that form the calvaria (skullcap) have two layers of compact bone called plates (tables), separated by a thicker layer of spongy bone called the diploë.

Microscopic examination of bone shows two types: immature primarybone and mature secondarybone (Figure 8–8).

 

 

 

 

Primary Bone Tissue

Primary bone is the first bone tissue to appear in embryonic development and in fracture repair. It is characterized by random disposition of fine collagen fibers and is therefore often called woven bone (Figure 8–8). Primary bone tissue is usually temporary and is replaced in adults by secondary bone tissue except in a very few places in the body, eg, near the sutures of the calvaria, in tooth sockets, and in the insertions of some tendons.

In addition to the irregular array of collagen fibers, other characteristics of primary bone tissue are a lower mineral content (it is more easily penetrated by x-rays) and a higher proportion of osteocytes than that in secondary bones.

 

 

Secondary Bone Tissue

Secondary bone tissue is the type usually found in adults. It characteristically shows multiple layers of calcified matrix (each 3–7 m thick) and is often referred to as lamellar bone. The lamellae are quite organized, either parallel to each other or concentrically around a vascular canal. Each complex of concentric bony lamellae surrounding a small canal containing blood vessels, nerves, and loose connective tissue is called an osteon (formerly known as an haversian system) (Figures 8–1 and 8–9). Lacunae with osteocytes are found between the lamellae, interconnected by canaliculi which allow all cells to be in contact with the source of nutrients and oxygen in the osteonic canal (Figure 8–9). The outer boundary of each osteon is a more collagen-rich layer called the cement line.

 

 

 

 

 

In each lamella, type I collagen fibers are aligned in parallel and follow a helical course. The pitch of the helix is, however, different for different lamellae, so that at any given point, fibers from adjacent lamellae intersect at approximately right angles (Figure 8–1). The specific organization of collagen fibers in successive lamellae of each osteon is highly important for the great strength of secondary bone.

In compact bone (eg, the diaphysis of long bones) besides forming osteons, the lamellae also exhibit a typical organization consisting of multiple external circumferential lamellae (Figure 8–1) and often some inner circumferential lamellae. Inner circumferential lamellae are located around the marrow cavity and external circumferential lamellae are located immediately beneath the periosteum.

Each osteon is a long, often bifurcated cylinder generally parallel to the long axis of the diaphysis. It consists of a central canal surrounded by 4–10 concentric lamellae. Each endosteum-lined canal contains blood vessels, nerves, and loose connective tissue. The central canals communicate with the marrow cavity and the periosteum and with one another through transverse or oblique perforating canals (formerly known as Volkmann canals) (Figures 8–1 and 8–10). The transverse canals do not have concentric lamellae; instead, they perforate the lamellae. All osteonic and perforating canals in bone tissue come into existence when matrix is laid down around preexisting blood vessels.

 

 

 

 

 

Among the osteons between the two circumferential systems are numerous irregularly shaped groups of parallel lamellae called interstitial lamellae. These structures are lamellae remaining from osteons partially destroyed by osteoclasts during growth and remodeling of bone (Figure 8–10).

Bone remodeling is continuous throughout life and involves a combination of bone synthesis and removal. In compact bone, remodeling resorbs parts of old osteons and produces new ones. Resorption involves the actions of osteoclasts, often working in groups to remove old bone in tunnel-like cavities having the approximate diameter of new osteons. Such tunnels are quickly invaded by many osteoprogenitor cells and sprouting loops of blood capillaries, both derived from the endosteum or periosteum. Osteoblasts develop, line the wall of the tunnels, and begin to secrete osteoid in a cyclic manner, forming concentric lamellae of bone with trapped osteocytes (Figure 8–11). In healthy adults 5–10% of the bone turns over annually.

 

 

 

 

Variations in the remodeling activity produce great variability in the sizes of osteons, osteonic canals, and interstitial lamellae. As osteons form by successive deposition of lamellae by osteoblasts, moving inward from the periphery, younger osteons usually have larger canals. In mature osteons the most recently formed lamella is the one closest to the central canal.

 

 

Osteogenesis

Bone can be formed initially by either of two ways:

§         Intramembranous ossification, in which osteoblasts differentiate directly from mesenchyme and begin secreting osteoid

§         Endochondral ossification, in which the matrix of preexisting hyaline cartilage is eroded and replaced by osteoblasts producing osteoid.

In both processes, the bone tissue that appears first is primary or woven. Primary bone is a temporary and is soon replaced by the definitive secondary lamellar bone. During bone growth, areas of primary bone, areas of resorption, and areas of secondary bone all appear side by side.

 

 

Intramembranous Ossification

Intramembranous ossification, by which most flat bones are produced, is so called because it takes place within condensations of embryonic mesenchymal tissue. The frontal and parietal bones of the skull—as well as parts of the occipital and temporal bones and the mandible and maxilla—are formed by intramembranous ossification. The process is summarized in Figure 8–12.

 

 

 

 

 

In the mesenchymal condensation layer or "membrane," the starting point for bone formation is called an ossification center. The process begins when groups of mesenchymal cells differentiate into osteoblasts. Osteoblasts produce osteoid matrix and calcification follows, resulting in the encapsulation of some osteoblasts, which then become osteocytes. These islands of developing bone form walls that delineate elongated cavities containing capillaries, bone marrow cells, and undifferentiated cells. Several such groups arise almost simultaneously at the ossification center, and their fusion between the walls gives the bone a spongy appearance. The connective tissue that remains among the bone walls is penetrated by growing blood vessels and additional undifferentiated mesenchymal cells, giving rise to the bone marrow. The ossification centers of a bone grow radially and finally fuse together, replacing the original connective tissue (Figures 8–12 and 8–13).

 

 

 

 

In cranial flat bones there is a marked predominance of bone formation over bone resorption at both the internal and external surfaces. Thus, two layers of compact bone (internal and external plates) arise, while the central portion (diploë) maintains its spongy nature. The fontanelles or "soft spots" on the heads of newborn infants are areas in the skull that correspond to parts of the connective tissue that are not yet ossified. The portions of the connective tissue layer that do not undergo ossification give rise to the endosteum and the periosteum of the new bone.

 

 

Endochondral Ossification

Endochondral (Gr. endon, within, + chondros, cartilage) ossification takes place within a piece of hyaline cartilage whose shape resembles a small version, or model, of the bone to be formed. This type of ossification is principally responsible for the formation of short and long bones.

Endochondral ossification of a long bone consists of the sequence of events shown schematically in Figure 8–14. Initially, the first bone tissue appears as a collar surrounding the diaphysis of the cartilage model. This bone collar is produced by local osteoblast activity within the surrounding perichondrium. The collar now impedes diffusion of oxygen and nutrients into the underlying cartilage, promoting degenerative changes there. The chondrocytes begin to produce alkaline phosphatase and swell up (hypertrophy), enlarging their lacunae. These changes both compress the matrix into narrower trabeculae and lead to calcification in these structures. Death of the chondrocytes results in a porous three-dimensional structure formed by the remnants of the calcified cartilage matrix (Figure 8–15). Blood vessels from the former perichondrium now the periosteum penetrate through the bone collar previously perforated by osteoclasts, bringing osteoprogenitor cells to the porous central region. Next, osteoblasts adhere to the calcified cartilage matrix and produce continuous layers of primary bone that surround the cartilaginous matrix remnants. At this stage, the calcified cartilage appears basophilic, and the primary bone is eosinophilic (Figure 8–15).

 

 

 

 

 

 

 

 

This process in the diaphysis forms the primary ossification center (Figure 8–14). Secondary ossification centers appear slightly later at the epiphyses of the cartilage model and develop in a similar manner. During their expansion and remodeling, the primary and secondary ossification centers produce cavities that are gradually filled with bone marrow.

In the secondary ossification centers, cartilage remains in two regions: the articular cartilage (Figure 8–14), which persists throughout adult life and does not contribute to bone growth in length, and the epiphyseal cartilage (also called epiphyseal plate or growth plate), which connects each epiphysis to the diaphysis (Figures 8–16 and 8–17). The epiphyseal cartilage is responsible for the growth in length of the bone and disappears in adults, which is why bone growth ceases in adulthood. Elimination of the epiphyseal plates ("epiphyseal closure") occurs at different times with different bones and is complete in all bones by about age twenty. In forensics or through X-ray examination of the growing skeleton, it is possible to determine the "bone age" of a young person, noting which epiphyses are open and which are closed. Once the epiphyses have closed, growth in length of bones becomes impossible, although bone widening may still occur.

 

 

 

 

 

 

 

A plate of epiphyseal cartilage is divided into five zones (Figure 8–16), starting from the epiphyseal side of cartilage:

1.      The resting zone consists of hyaline cartilage with typical chondrocytes.

2.      In the proliferative zone, chondrocytes begin to divide rapidly and form columns of stacked cells parallel to the long axis of the bone.

3.      The hypertrophic cartilage zone contains swollen chondrocytes whose cytoplasm has accumulated glycogen. Hypertrophy compresses the matrix into thin septa between the chondrocytes.

4.      In the calcified cartilage zone, loss of the chondrocytes by apoptosis is accompanied by calcification of the septa of cartilage matrix by the formation of hydroxyapatite crystals (Figure 8–17).

5.      In the ossification zone, bone tissue first appears. Capillaries and osteoprogenitor cells originating from the periosteum invade the cavities left by the chondrocytes. Many of these cavities will be merged and become the marrow cavity. The osteoprogenitor cells form osteoblasts, which settle in a discontinuous layer over the septa of calcified cartilage matrix. The osteoblasts deposit osteoid over the spicules of calcified cartilage matrix, forming woven bone (Figure 8–17).

In summary, growth in length of a long bone occurs by proliferation of chondrocytes in the epiphyseal plate adjacent to the epiphysis. At the same time, chondrocytes in the diaphyseal side of the plate hypertrophy, their matrix becomes calcified, and the cells die. Osteoblasts lay down a layer of primary bone on the calcified cartilage matrix. Because the rates of these two opposing events (proliferation and destruction) are approximately equal, the epiphyseal plate does not change thickness. Instead, it is displaced away from the middle of the diaphysis, resulting in growth in length of the bone.

 

 

Bone Growth, Remodeling, & Repair

Bone growth is generally associated with partial resorption of preformed tissue and the simultaneous laying down of new bone (exceeding the rate of bone loss). This process permits the shape of the bone to be maintained as it grows. The rate of bone remodeling (bone turnover) is very active in young children, where it can be 200 times faster than that in adults. Bone remodeling in adults is a dynamic physiologic process that occurs simultaneously in multiple locations of the skeleton and is not always related to bone growth.

Despite its hardness, the constant remodeling makes bone very plastic and capable of internal structural changes according to the various stresses to which it is subjected. A well-known example of bone plasticity is the ability of the positions of teeth in the jawbone to be modified by the lateral pressures produced by orthodontic appliances. Bone is formed on the side where traction is applied and is resorbed on the opposite side where pressure is exerted. In this way, teeth are moved within the jaw while the bone is being remodeled.

Cranial bones grow mainly because of the formation of bone tissue by the periosteum between the sutures and on the external bone surface. At the same time, resorption takes place on the internal surface. The plasticity of bone allows it to respond to the growth of the brain and form a skull of adequate size. The skull will be small if the brain does not develop completely and will be larger than normal in a person suffering from hydrocephalus, a disorder characterized by abnormal accumulation of spinal fluid and dilatation of the cerebral ventricles.

Because it contains osteoprogenitor stem cells throughout the endosteum and periosteum and has an extensive blood supply, bone has an excellent capacity for repair and regeneration. Bone fractures and other damage are repaired efficiently using cells and processes already active in bone remodeling. Surgically created gaps in bone can be filled with new bone, especially when periosteal tissue remains nearby.

 

 

MEDICAL APPLICATION

When a bone is fractured, blood vessels are disrupted and bone cells adjoining the fracture die. The damaged blood vessels produce a localized hemorrhage and form a blood clot.

Soon the blood clot is removed by macrophages and the adjacent matrix of bone is resorbed by osteoclasts. The periosteum and the endosteum at the site of the fracture respond with intense proliferation producing a soft callus of fibrocartilage-like tissue that surrounds the fracture and covers the extremities of the fractured bone (Figure 8–18).

Primary bone is then formed by a combination of endochondral and intramembranous ossification. Further repair produces irregularly formed trabeculae of primary bone that temporarily unite the extremities of the fractured bone, forming a hard bone callus (Figure 8–18).

Stresses imposed on the bone during repair and during the patient's gradual return to activity serve to remodel the bone callus. The primary bone of the callus is gradually resorbed and replaced by secondary bone, remodeling and restoring the original bone structure. Unlike other connective tissues, bone tissue heals without forming a scar.

 

 

 

 

Metabolic Role of Bone

Calcium ions are required for the activity of many enzymes and other proteins mediating cell adhesion, cytoskeletal movements, exocytosis, membrane permeability, and other functions in cells throughout the body. The skeleton serves as the calcium reservoir and contains 99% of the body's total calcium in crystals of hydroxyapatite. The concentration of calcium in the blood and tissues is generally quite stable because of a continuous interchange between blood calcium and bone calcium.

The principal mechanism for raising blood calcium levels is the mobilization of ions from hydroxyapatite crystals to interstitial fluid. This takes place mainly in cancellous bone. The younger, more lightly calcified lamellae that exist even in adult bone (because of continuous remodeling) receive and lose calcium more readily. These lamellae are more important for the maintenance of calcium concentration in the blood than are the older, more densely calcified lamellae, whose role is mainly that of support and protection.

The action of two key hormones on cells in bone regulates the process of calcium mobilization from hydroxyapatite. Parathyroid hormone (PTH) from the parathyroid glands raises low blood calcium levels. The principal target cells of this polypeptide are osteoblasts, which stop production of osteoid and matrix vesicles and instead secrete a paracrine protein, osteoclast stimulating factor. This factor promotes osteoclastic resorption of the bone matrix, liberating calcium. Osteoclast activity is inhibited by another hormone, calcitonin, which is synthesized by the parafollicular cells of the thyroid gland. This slows matrix resorption and thereby gradually lowers blood calcium levels.

 

 

MEDICAL APPLICATION

Because the concentration of calcium in tissues and blood must be kept constant, nutritional deficiency of calcium results in decalcification of bones. Severely decalcified bones are more likely to fracture.

Decalcification of bone may also be caused by excessive production of PTH (hyperparathyroidism), which can cause increased osteoclastic activity, intense resorption of bone, elevation of blood Ca2+ and PO3– 4 levels, and abnormal deposits of calcium in the kidneys and arterial walls.

The opposite occurs in osteopetrosis (L. petra, stone), a disease caused by defective osteoclast function that results in overgrowth, thickening, and hardening of bones. This process can obliterate the bone marrow cavities, depressing blood cell formation and causing anemia and the loss of white blood cells.

 

 

Nutritional Deficiencies and Bone Remodeling

Especially during growth, bone is sensitive to nutritional factors. Calcium deficiency, which leads to incomplete calcification of the organic bone matrix, can be due either to a lack of calcium in the diet or a failure to produce the steroid prohormone vitamin D, which is important for the absorption of Ca2+ and> PO3–4 by the small intestine.

Calcium deficiency in children causes rickets, a disease in which the bone matrix does not calcify normally and the epiphyseal plate becomes distorted by the normal strains of body weight and muscular activity. Ossification processes at this level are consequently hindered, and the bones not only grow more slowly but also become deformed.

Calcium deficiency in adults gives rise to osteomalacia (osteon + Gr. malakia, softness), which is characterized by deficient calcification of recently formed bone and partial decalcification of already calcified matrix. Osteomalacia should not be confused with osteoporosis. In osteomalacia, there is a decrease in the amount of calcium per unit of bone matrix. Osteoporosis, frequently found in immobilized patients and in postmenopausal women, is an imbalance in skeletal turnover so that bone resorption exceeds bone formation.

 

 

Hormones Acting on Bone Tissue

In addition to PTH and calcitonin, several other hormones act on bone. The anterior lobe of the pituitary synthesizes growth hormone (GH or somatotropin), which stimulates the liver to produce insulin-like growth factor-1 (IGF-1 or somatomedin). IGF has an overall growth effect, especially on the epiphyseal cartilage. Consequently, lack of growth hormone during the growing years causes pituitary dwarfism; an excess of growth hormone causes excessive growth of the long bones, resulting in gigantism. Adult bones cannot increase in length even with excess IGF because they lack epiphyseal cartilage, but they do increase in width by periosteal growth. In adults, an increase in GH causes acromegaly, a disease in which the bones—mainly the long ones—become very thick.

The sex hormones, both male (androgens) and female (estrogens), have a complex effect on bones and are, in a general way, stimulators of bone formation. They influence the time of appearance and development of ossification centers and accelerate the closure of epiphyses.

 

 

Bone Tumors

Cancer originating directly from bone cells is fairly uncommon (0.5% of all cancer deaths) but a form called osteosarcoma can arise in osteoblasts. The skeleton is often the site of metastases from tumors originating from malignancies in other organs, most commonly from breast, lung, prostate, kidney, and thyroid tumors.

 

 

Joints

Joints are regions where bones are capped and surrounded by connective tissues that firmly hold the bones together and determine the type and degree of movement between them. Joints may be classified as diarthroses, which permit free bone movement, and synarthroses (Gr. syn, together, + arthrosis, articulation), in which very limited or no movement occurs. There are three types of synarthroses, based on the type of tissue uniting the bone surfaces:

§         Synostoses, in which bones are united by bone tissue and no movement takes place. In older adults, synostoses unite the skull bones, which, in children and young adults, are united only by dense connective tissue

§         Synchondroses, in which the bones are joined by hyaline cartilage. The epiphyseal plates of growing bones are one example and in adults a synchondrosis unites the first rib to the sternum, with little movement

§         Syndesmoses, in which bones are joined by an interosseous ligament of dense connective tissue or fibrocartilage (eg, the pubic symphysis, Figure 7–1), again with very limited movement.

Diarthroses (Figure 8–19) are joints that generally unite long bones and have great mobility, such as the elbow and knee joints. In a diarthrosis, ligaments and a capsule of dense connective tissue maintain proper alignment of the bones. The capsule encloses a sealed joint cavity that contains synovial fluid, a colorless, transparent, viscous fluid. The joint cavity is not lined by epithelium, but by a specialized connective tissue called the synovial membrane which extends folds and villi into the cavity and secretes the lubricant synovial fluid. Synovial fluid is derived from blood plasma, but with a high concentration of hyaluronic acid produced by cells of the synovial membrane.

 

 

 

 

 

The synovial membrane or layer may have prominent regions with various types of connective tissue (areolar, fibrous, or adipose) in different diarthrotic joints. At the surface contacting the synovial fluid the tissue is usually well-vascularized, with many porous (fenestrated) capillaries, and contains two specialized cells (synoviocytes) with distinctly different functions and origins (Figure 8–20). Rounded synoviocytes in contact with the synovial cavity are phagocytic and remove wear-and-tear debris from the synovial fluid. Among the capillaries are many more fibroblastic synoviocytes specialized to produce the long, nonsulfated glycosaminoglycan (GAG) hyaluronic acid and secrete other components of ground substance. These GAGs along with plasma from the capillaries leave the synovial membrane, oozing into the synovial fluid. This viscous, gel-like fluid lubricates the joint, reducing friction on all internal surfaces, and supplies nutrients and oxygen to the articular cartilage.

 

 

 

 

 

The collagen fibers of the hyaline articular cartilage are disposed as arches with their tops at the exposed surface, which unlike most cartilage is not covered by perichondrium (Figure 8–21). This arrangement of collagen helps to distribute more evenly the forces generated by pressure on joints. The resilient articular cartilage is also an efficient absorber of the intermittent mechanical pressures to which many joints are subjected.

 

 

 

 

 

A similar mechanism is seen in intervertebral disks (Figure 8–22) which are thick disks of fibrocartilage between the articular surfaces of successive bony vertebrae. The annulus fibrosus of each disk has an external layer of dense connective tissue, but is mainly composed of overlapping laminae of fibrocartilage in which collagen bundles are orthogonally arranged in adjacent layers. The multiple lamellae, with the 90-degree registration of type I collagen fibers in adjacent layers, provide the disk with unusual resilience that enables it to withstand the pressures generated by the impinging vertebrae.

 

 

 

 

The nucleus pulposus is situated in the center of the annulus fibrosus. It may contain a few scattered cells derived from the embryonic notochord, but is largely composed of viscous, gel-like matrix rich in hyaluronic acid and fibers of type II collagen. The nucleus pulposus is large in children, but gradually becomes smaller with age and is partially replaced by fibrocartilage. The nucleus pulposus allows each intervertebral disk to function as a shock absorber within the spinal column.

 

 

MEDICAL APPLICATION

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