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14.4
The emergence of bone cells
  Under the extremes of pressure, het and climactic conditions of earlier periods of Earth, the bone cell is the emergence of yet another specialized cell from the "proto skin" cells hundreds of millions of years ago. In not only providing the internal strength and support to withstand tremendous pressures, this type of cell created ultimately the "perfect" universe for cells- one tightly protected from any external extreme elements. In such environments, some of the most specialized cells of all accomplished the task of creating new semi-complete cells.  
  BONE is a rigid body tissue consisting of cells embedded in an abundant, hard intercellular material. The two principal components of this material, collagen and calcium phosphate, distinguish bone from such other hard tissues as chitin, enamel, and shell.  
  The functions of bone include (1) structural support for the mechanical action of soft tissues, such as contraction of muscles, expansion of lungs; (2) protection of soft parts, as by the brain case; (3) provision of a protective site for specialized tissues such as the blood-forming system (bone marrow); and (4) a mineral reservoir or sink, whereby endocrine systems regulate the level of calcium and phosphate in the circulating body fluids.  
14.4.1 Evolutionary origin and significance
  Bone is found only in vertebrates, and, among modern vertebrates, only in bony fish and higher classes. Although fossil ancestors of the elasmobranchs and cyclostomes had armoured head cases, serving largely a protective function, which appear to have been true bone, modern cyclostomes have only an endoskeleton, or inner skeleton, of non calcified cartilage, and elasmobranchs, a skeleton of calcified cartilage. Although a rigid endoskeleton performs obvious body supportive functions for land-living vertebrates, it is doubtful that bone offered any such mechanical advantage to the teleost (bony fish) in which it first appeared, for in a supporting aquatic environment, great structural rigidity is not essential for maintaining body configuration. The sharks and rays are superb examples of mechanical engineering efficiency, and their perseverance from the Devonian attests to the suitability of their non bony endoskeleton.  
  In modern vertebrates true bone is found only in animals also capable of controlling the osmotic and ionic composition of their internal fluid environment.  
  Marine invertebrates exhibit interstitial fluid compositions essentially the same as that of the surrounding sea water. Early signs of regulability are seen in cyclostomes and elasmobranchs, but only at or above the level of true bone fishes does the composition of the internal body fluids become constant. The mechanisms involved in this regulation are many and complex and include both the kidney and the gills. Fresh and marine waters provide abundant calcium, but only traces of phosphate, and, because relatively high levels of phosphate are characteristic of the body fluids of higher vertebrates, it seems likely that a large, readily available internal phosphate reservoir would confer significant independence of external environment on bony vertebrates. With the emergence of terrestrial forms, the availability of calcium regulation became equally significant. Along with the kidney and the various component glands of the endocrine system, bone has contributed to development of internal fluid homeostasis--the maintenance of a constant chemical composition. This was a necessary step for emergence of land-living vertebrates. Moreover, out of the buoyancy of water, structural rigidity of bone afforded mechanical advantages that are the most obvious features of the modern vertebrate skeleton.  
14.4.2 Chemical composition and physical properties  
  Depending upon species, age, and type of bone, the bone cells represent 1-15 percent of the volume of bone, but in mature bone in most higher animals usually they represent 1-5 percent. The nonliving intercellular material consists of an organic component, collagen (a fibrous protein arranged in long strands or bundles similar in structure and organization to the collagen of ligaments, tendons, and skin), with small amounts of protein polysaccharides, mucopolysaccharides chemically bound to protein and dispersed within and around the collagen fibre bundles, and an inorganic mineral component in the form of innumerable rod-shaped crystals with diameters on the order of 50 and lengths from 200 to 2,000 . These crystals are arranged parallel with the long axes of collagen bundles and many actually lie in voids within the bundles themselves. Organic material comprises 50 percent of the volume and 30 percent of the dry weight of the intercellular composite, and mineral the remainder. The major minerals are calcium and phosphate, present in proportions ranging from 1.4:1 to 2.1:1. When first deposited, mineral is crystallographically amorphous but with maturation becomes typical of the apatite minerals, the major component being hydroxyapatite, Ca10(PO4)6(OH)2. Carbonate is also present, in amounts varying from 4 percent of bone ash in fish and 8 percent in most mammals to more than 13 percent in the turtle, and occurs in two distinct phases, calcium carbonate and a carbonate apatite. Except for that associated with its cellular elements, there is little free water in adult mammalian bone (approximately 8 percent of total volume). As a result, diffusion from surfaces into the interior of the intercellular substance occurs at the slow rates more typical of diffusion from surfaces of solids than within liquids.  
  The structural role of the skeleton depends on the hardness, strength, and rigidity of bone. The mineral crystals are responsible for hardness, rigidity, and the great compressive strength of bone, but they share with other crystalline materials a great weakness in tension, arising from the tendency for stress to concentrate about defects and for these defects to propagate. On the other hand, the collagen fibrils of bone possess high elasticity, little compressive strength, and considerable intrinsic tensile strength. The tensile strength of bone depends, however, not on collagen alone but on the intimate association of mineral with collagen, which confers on bone many of the general properties exhibited by two-phase materials such as fibre glass and bamboo. In such materials the dispersion of a rigid but brittle material in a matrix of quite different elasticity prevents the propagation of stress failure through the brittle material and hence allows a closer approach to the theoretical limiting strength of single crystals.  
  The fine structure of bone has thus far frustrated attempts to determine the true strength of the mineral-matrix composite at the "unit" structural level. Compact bone specimens have been found to have tensile strength in the range of 700-1,400 kilograms per square centimetre (10,000-20,000 pounds per square inch), and compressive strengths in the range of 1,400-2,100 kilograms per square centimetre (20,000-30,000 pounds per square inch). These values are of the same general order as for aluminum or mild steel, but bone has an advantage over such materials in that it is considerably lighter. The great strength of bone exists principally along its long axis and hence roughly parallel both to the collagen fibre axis and to the long axis of the mineral crystals.  
  Although apparently stiff, bones exhibit a considerable degree of elasticity, which is important to the skeleton's ability to withstand impact. Estimates of modulus of elasticity of bone samples are of the order of 420 to 700 kilograms per square centimetre (6,000 to 10,000 pounds per square inch), a value very much less than steel, for example, indicating much greater elasticity of bone. Perfect elasticity exists with loads up to 30 to 40 percent of breaking strength; above this, creep occurs, presumably along natural defects within the bony structure. The modulus of elasticity in bone is strikingly dependent upon the rate at which loads are applied, bones being stiffer during rapid deformation than during slow; this behaviour suggests an element of viscous flow during deformation.  
  As might be anticipated from consideration of the two-phase composition of bone, variation in the mineral-collagen ratio leads to change in physical properties: less mineral tends ultimately to greater flexibility, and more mineral to increased brittleness. Optimal ratios, as reflected in maximal tensile strength, are observed at an ash content of approximately 66 percent, a value that is characteristic of the weight-bearing bones of mammals  
14.4.3 Bone morphology  
  Grossly, bone tissue is organized into a variety of shapes and configurations adapted to the function of the bone concerned: broad, flat plates, such as scapula, as anchors for large muscle masses, or hollow, thick-walled tubes, such as femur, radius, ulna, for supporting weight or for use as a lever arm. These different types of bone are distinguished more by their external shape than by their basic structure.  
  In all bones the basic bone has an exterior layer, termed cortex, that is smooth, dense, continuous, and of varying thickness. In its interior, bony tissue is arranged in a network of intersecting plates and spicules, varying in amount in different bones, enclosing spaces filled with blood vessels and marrow. This honeycombed bone is termed cancellous, and the plates and spicules trabeculae. In mature bone, trabeculae are arranged in an orderly pattern that provides continuous units of bony tissue aligned parallel with the lines of major compressive or tensile force. Trabeculae thus provide a complex series of cross-braced interior struts so arranged as to give maximal rigidity with minimal material.  
  Bones such as vertebrae, subject to primarily compressive or tensile forces, usually have thin cortices and provide necessary structural rigidity through trabeculae; whereas bones such as the femur, subject to prominent bending, shear, or torsional forces, usually have thick cortices, a tubular configuration, and a continuous cavity running through their centres (medullary cavity). The cortical material of tubular bones is termed compact bone and differs in a number of fine structural details from cancellous bone.  
  Long bones, distinctive of the body's extremities, exhibit a number of gross structural features in common. The central region of the bone (diaphysis) is the most clearly tubular. At one or commonly both ends the diaphysis flares outward and assumes a predominantly cancellous internal structure. This region (metaphysis) functions to transfer loads from weight-bearing joint surfaces to the diaphysis. Finally, at the end of a long bone is a region known as an epiphysis, which exhibits a cancellous internal structure and which comprises the bony substructure of the joint surface. Prior to full skeletal maturity the epiphysis is separated from the metaphysis by a cartilaginous plate, the growth plate or physis; in bones with complex articulations (such as the humerus at its lower end) or bones with multiple protuberances (such as the femur at its upper end) there may be several separate epiphyses, each with its growth plate.  
14.4.4 Four types of cells in bone  
  Microscopically, bone consists of hard, apparently homogeneous intercellular material, within or upon which can be found four characteristic cell types: osteoblast, osteocyte, osteoclast, and undifferentiated bone mesenchymal cells. The osteoblast is responsible for the synthesis and deposition on bone surfaces of the protein matrix of new intercellular material. The osteocyte is an osteoblast that has been trapped within intercellular material, residing in a cavity (lacuna) and communicating with other osteocytes as well as with free bone surfaces by means of extensive filamentous protoplasmic extensions that occupy long, meandering channels (canaliculi) through the bone substance. With the exception of certain higher orders of modern fish, all bone, including primitive vertebrate fossil bone, exhibits an osteocytic structure. Osteoclasts are usually large, multinucleated cells that, working from bone surfaces, resorb bone by direct chemical and enzymatic attack. Undifferentiated mesenchymal cells of the bone reside in the loose connective tissue between trabeculae, along vascular channels, and in the condensed fibrous tissue covering the outside of the bone (periosteum); they give rise under appropriate stimuli to either osteoblasts or osteoclasts.  
  Depending on how the protein fibrils and osteocytes of bone are arranged, bone is of two major types: woven, in which collagen bundles and the long axes of the osteocytes are randomly oriented, and lamellar, in which both the fibrils and osteocytes are aligned in clear layers. In lamellar bone the layers alternate every few microns, and the primary direction of the fibrils shifts approximately 90. In compact bone of many mammalian species, lamellar bone is further organized into units known as osteons, or haversian systems, which consist of concentric cylindrical lamellar elements several millimetres long and 0.2-0.3 millimetre (0.008-0.012 inch) in diameter. Osteons exhibit a gently spiral course oriented along the axis of the bone. In their centre is a canal (haversian canal) containing one or more small blood vessels, and at their outer margins is a boundary layer known as a "cement line," which serves both as a means of fixation for new bone deposited on an old surface and as a diffusion barrier. Osteocytic processes do not penetrate the cement line, and hence these barriers constitute the outer envelope of a nutritional unit, osteocytes on opposite sides of a cement line deriving their nutrition from different vascular channels. Cement lines are found in all types of bone, as well as in osteons, and in general they indicate lines at which new bone was deposited on an old surface.  
  In a typical long bone, blood is supplied by three separate systems: nutrient artery, periosteal vessels, and epiphyseal vessels. The diaphysis and metaphysis are nourished primarily by the nutrient artery, which passes through the cortex into the medullary cavity and then ramifies outward through haversian and Volkmann's canals to supply the cortex. Extensive vessels in the periosteum, the membrane surrounding the bone, supply the superficial layers of the cortex and connect with the nutrient-artery system. In the event of obstruction of the nutrient artery, periosteal vessels are capable of meeting the needs of both systems. The epiphyses are supplied by a separate system that consists of a ring of arteries entering the bone along a circular band between the growth plate and the joint capsule. In the adult these vessels become connected to the other two systems at the metaphyseal-epiphyseal junction, but while the growth plate is open there is no such connection, and the epiphyseal vessels are the sole source of nutrition for the growing cartilage; hence they are essential for skeletal growth.  
  Drainage of blood is by a system of veins that runs parallel with the arterial supply and by veins leaving the cortical periosteum through muscle insertions. Muscle contraction milks blood outward, giving rise to a centrifugal pattern of flow from the axial nutrient artery through the cortex and out through muscle attachments.  
14.4.5 Remodeling, growth, and development  
  Whereas renewal in tissues such as muscle occurs largely at a molecular level, renewal of bone occurs at a tissue level and is similar to the Remodeling of buildings in that local removal (resorption) of old bone must precede new bone deposition. Remodeling is most vigorous during the years of active growth, when deposition predominates over resorption. Thereafter Remodeling gradually declines, in humans until about age 35, after which its rate remains unchanged or increases slightly. From the fourth decade on, resorption exceeds formation, resulting in a 5-10 percent loss in bone mass per decade, equivalent to a daily loss of 15-30 milligrams of calcium.  
  Except for the addition of the ossification mechanisms within cartilage, growth and development involve exactly the same type of Remodeling as that in the adult skeleton. Both require continuous, probably irreversible differentiation of osteoclasts and osteoblasts from the undifferentiated bone mesenchyme. Life span of osteoclasts is from a few hours to at most a few days, that of osteoblasts a few days to at most a few weeks.  
  Resorption is produced by clusters of osteoclasts that either erode free bone surfaces or form "cutting cones" that tunnel through compact bone and create the cylindrical cavities that may be subsequently filled by osteons. Osteoclastic cells secrete enzymes and hydrogen ions onto the bone surface, dissolving the mineral and digesting the matrix at virtually the same moment. The process is associated with locally augmented blood flow and with a greater surface acidity than elsewhere in bone, despite the fact that the process of dissolving apatite consumes hydrogen ions. Resorption is usually a much more rapid process than formation. Osteoclastic cutting cones have been observed to advance at rates up to 500 microns per day (one micron = 1 10-3 millimetre).  
  Bone is formed on previously resorbed surfaces by deposition of a protein matrix material (osteoid) and its subsequent mineralization. Osteoblasts elaborate matrix as a continuous membrane covering the surface on which they are working at a linear rate that varies with both age and species but which in large adult mammals is on the order of 1.0 micron per day. The unmineralized matrix constitutes an osteoid seam or border, averaging 6 to 10 microns in thickness during active bone formation. The biochemical and physical sequence of events that prepare matrix for mineralization includes intracellular biosynthesis of collagen by osteoblasts, extrusion of collagen extracellularly in soluble form, maturation or polymerization of collagen into an array of fibrils (in random orientation in rapidly deposited bone, in a highly ordered, regular pattern in slowly formed lamellar bone), binding of calcium to collagen fibrils, and formation of protein-mucopolysaccharide complexes. Mineralization itself depends upon establishment of crystal nuclei within the matrix; this process requires five to ten days and is under the control of the osteoblast, but its exact chemistry is obscure. A suitable nucleating configuration is somehow established, and once nuclei reach a critical size further mineralization proceeds spontaneously in the presence of usual body fluid calcium and phosphorus concentrations. Other collagenous tissues, such as dermis, tendon, and ligament, do not normally calcify, even though bathed by the same body fluids as bone. Although extracellular fluid is a highly supersaturated solution with respect to hydroxylapatite, calcium and phosphorus will not spontaneously precipitate in this crystalline form at normal physiological pH, so that one and the same fluid is indefinitely stable in non-bone-forming regions yet richly supports mineralization in the presence of suitable crystal nuclei. Mineral movement into new bone is initially rapid and in compact cortical bone is known to reach approximately 70 percent of full mineralization within a few hours after matrix nucleation. This mineral deposition involves replacement of the water that occupied half the original matrix volume. As water content falls, further mineral diffusion is impeded; and the final mineralization occurs progressively more slowly over a period of many weeks. In normal adult humans new bone formation takes up about 400 milligrams of calcium per day, an amount approximately equal to that in the circulating blood.  
  Osteocytes, once thought of as resting cells, are now recognized to be metabolically active and to possess, at least in latent form, the ability to resorb and reform bone on their lacunar walls. Although osteocytes constitute only a small fraction of total bone volume, they are so arranged within bone, and the network of their protoplasmic extensions is so extensive that there is essentially no volume of bony material situated more than a fraction of a micron from a cell or its processes. Of the more than 1,200 square metres (1,435 square yards) of anatomic surface within the skeleton of an adult man, about 99 percent is accounted for by the lacunar and canalicular surfaces. Resorption and deposition on this surface serve both to regulate plasma-calcium concentration and to renew bony material. This renewal may be particularly important because all composite materials change in their physical properties with time. It is not known whether bone properties change sufficiently to have biologic consequence, but to the extent that such change does occur, renewal around osteocytes would provide for the physical maintenance of bone structural material.  
14.4.6 Types of bone formation  
  Bone is formed in the embryo in two general ways. For most bones the general shape is first laid down as a cartilage model, which is then progressively replaced by bone (endochondral bone formation). A few bones (such as clavicle and calvarium) develop within a condensed region of fibrous tissue without a cartilaginous intermediate (membrane bone formation). In long bones a collar of spongy membrane bone is first laid down in the fibrous tissues surrounding the cartilaginous model of the shaft. At the same time the cartilage deep to this collar begins to degenerate and calcify. The bone is then penetrated by blood vessels, which grow into the degenerating model and remove the calcified cartilage enclosed within the collar. Vascular invasion proceeds toward both ends of the model in parallel with continued extension of the bony collar. This leaves a structure consisting of two cartilaginous epiphyses at the ends of a hollow, bony shaft.  
  Growth from this point on is accomplished in two ways. Radial growth occurs by deposition of new bone on the periosteal surface and roughly equivalent resorption at the endosteal surface. Longitudinal growth involves replacement of cartilage by bone from the shaft side of the growth plate, at a rate closely matched to the production of new cartilage by the plate itself. The growth plate consists of highly ordered rows of cartilage cells; the row farthest removed from the bony shaft is a basal or germinal layer; it is responsible for cell replication and cartilage growth. The complex sequence of longitudinal growth consists of cartilage cell degeneration farthest from the germinal layer, calcification of cartilage in that area, deposition over it of a thin layer of true bone (primary spongiosa), and, finally, osteoclastic resorption to extend the medullary cavity in parallel with longitudinal growth and to reshape the contour of the shaft.  
  Cartilage growth, degeneration, calcification, and ultimate replacement by bone is responsible for most growth in length in vertebrates. It first begins in the embryo and continues until full skeletal maturity, when in most species the growth plates fuse and disappear.  
  The appearance of epiphyseal ossification centres and their ultimate fusion, both of which can be detected by ordinary X-rays, normally follows an orderly and predictable sequence that is of great value in the evaluation of disorders of growth and development. Because of the complicated interaction of several tissue elements in the process of endochondral ossification, the metaphyseal region of bones is the seat of, or prominently reflects, many nutritional or metabolic disturbances of growth. Examples of disorders involving this growth mechanism include rickets and achondroplastic dwarfism.  
14.4.7 Hormonal influences  
  The most striking effects of estrogens are seen in birds, in which during the part of the cycle prior to egg formation a marked increase in osteoblastic activity occurs along the inside surfaces of the long bones, and the medullary cavities become filled with spongy bone. As the egg is formed, this spongy bone is rapidly resorbed, plasma calcium rises dramatically, and calcium is deposited in the shell. In mammals studied prior to skeletal maturity, administration of estrogens produces an accelerated appearance of ossification centres, a slowing in growth of cartilage and bone, and fusion of the epiphyses; the result is an adult skeleton smaller than normal. In older mammals estrogens in certain dosages and schedules of administration may inhibit trabecular bone resorption, and in some species prolonged administration of estrogen may lead to increased bone porosity. In postmenopausal women administration of estrogen suppresses bone resorption and produces a transient decrease in serum calcium and phosphorus and in renal reabsorption of phosphorus, as well as positive calcium balance, effects which help to stabilize the total skeletal bone mass.  
  The effects described are for estrogens as a general class of steroid hormone, and no attempt has been made to differentiate between the actions of natural estrogenic hormones and the many synthetic varieties now in wide use to suppress ovulation. Extremely few studies have been conducted to determine the effects of the latter on bone.  
  Very little is known of the effects of progesterone on bone beyond studies in young guinea pigs suggesting slight inhibition of the activity of such hormones as estrogens, which speed skeletal development.  
  In mammals, including humans, just prior to sexual maturity, the growth spurt occurring in males is attributable principally to the growth-promoting action of the male sex hormone testosterone. When administered, testosterone and related steroids stimulate linear growth for a limited period; ultimately, however, particularly if they are given in large doses, they suppress bone growth as the result of hastened skeletal development and premature epiphyseal closure. Studies have indicated that testosterone derivatives administered to adult mammals suppress the turnover and resorption of bone and increase the retention of nitrogen, phosphorus, and calcium.  
  The influence of the adrenal corticosteroid hormones on bone is varied, but the principal result is slowing of growth in the young and decrease in bone mass in the adult. In Cushing's syndrome, in which there is abnormally high secretion of corticosteroids, bone loss to the point of fractures often occurs. Cortisol in high concentration suppresses protein and mucopolysaccharide synthesis, with inhibition of bone matrix formation and of incorporation of nucleosides into bone cells.  
  Lack of the internal secretion of the thyroid gland results in retardation of skeletal growth and development. Action of this hormone to facilitate growth and skeletal maturation is probably indirect, through its general effects on cell metabolism. Thyroid hormone in excess leads in the young to premature appearance of ossification centres and closure of the epiphyses, and in the adult to increased bone-cell metabolism. Commonly in the hyperthyroid adult bone resorption predominates over increased bone formation with resultant loss of bone mass.  
  The anterior lobe of the pituitary gland secretes a hormone essential for growth and development of the skeleton. This effect of the hormone is indirect and mediated by "sulfation factor," a substance produced in the liver in response to stimulation by the growth hormone. The extent to which growth hormone is involved in skeletal remodelling in the adult is not known, but excessive elaboration of the hormone after maturity leads to distorted enlargement of all bones in the condition known as acromegaly. Excessive elaboration of growth hormone prior to epiphyseal closure leads to gigantism. Studies of the administration of growth hormone to man have indicated marked species specificity; growth in hypopituitary dwarfs is stimulated only by human or primate growth hormone. The principal metabolic effects in man of the hormone are retention of nitrogen and increased turnover of calcium, resulting in increases both in intestinal calcium absorption and in urinary calcium excretion.  
  Insulin participates in the regulation of bone growth; it may enhance or even be necessary for the effect of growth hormone on bone. Insulin has been found to stimulate growth and epiphyseal widening in rats whose pituitaries have been removed and to promote chondroitin sulfate synthesis in cartilage and bone and the transport of amino acids and nucleosides into bone.  
     
 
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