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Зміст23.2 The physiology of bone
508 23 The control of growth
23 The control of growth
23.5 The role of other hormones in the process of growth
512 23 The control of growth
23.6 Growth of cells, tissues, and organs
23.6 Growth of cells, tissues, and organs
The control of growth
All biological tissues are made up of cells. Life begins as a single cell, the fertilized egg, from which all the diverse cell types of the body arise within a few weeks. Very early in development, cells begin to specialize and develop into particular types—liver cells, nerve cells, epithelial cells, muscle cells, and so on. Each cell type has its appropriate place within the organism. This development of specific and distinctive features is known as differentiation. Differentiated cells maintain their specialized character and pass it on to their progeny.
Overall growth of the body involves an increase in size and weight of the body tissues with the deposition of additional protein, and is thus a measurable quantitative change. In contrast, development occurs through a series of coordinated qualitative changes that affect the complexity and function of body tissues. Developmental change is most rapid while an individual is young and it results in a normally developed adult man or woman. Growth and development are complex processes that are influenced by a number of different factors, both genetic and environmental. It is believed that genetic factors both lay down the basic guidelines for overall height achieved (as indicated by the correlation of adult height between parents and children) and set the pattern and timing of growth spurts.
The major influence superimposed upon the genetic make-up of an individual is probably nutritional, although illness, trauma, and other socio-economic factors can also modify the processes involved in growth. A child who has a diet that is inadequate, either with regard to its quality or quantity, will be unlikely to achieve his or her full genetic potential in terms of adult height. Indeed, improved nutrition is cited as one of the most important factors in the overall increase in stature which has been noted in Western societies over the past century.
Growth occurs at the level of individual cells, populations of cells (the tissues and organs), and at the level of the whole body. The underlying processes are regulated by a number of different hormones, including growth hormone, thyroid hormones, and sex steroids. The general properties of these hormones have been discussed in Chapter 12 and only those aspects of endocrine activity which relate specifically to growth will be considered in this chapter. Overall body growth will be considered first, and given the greatest emphasis. Detailed discussion of the many
factors believed to be responsible for the development and maintenance of appropriately sized populations of differentiated cells is beyond the scope of this book. Nevertheless, the importance of tissue growth and the factors that control the overall size of cell populations cannot be ignored and a brief overview, including abnormalities of cell and tissue growth, will be given at the end of the chapter.
Patterns of growth during fetal life
The period of prenatal growth is of great importance to an individual's future well-being. The development of sensitive ultrasound techniques has meant that it is now possible to monitor fetal size throughout most of pregnancy. Measurements of abdominal circumference, femur length, and biparietal diameter (the distance across the head measured from one ear to the other) are commonly taken to assess the increasing size of the fetus. Figure 23.1 shows that the rate of increase in body length is at its greatest at around 16-20 weeks' gestation. Prior to this, particularly during the so-called embryonic period (the first 10 weeks of gestation), growth velocity is lower, and there is a greater emphasis on differentiation of body parts such as the head, arms, and legs, and of cells into specialized tissues such as muscle and nerve. Each region is molded into a definite shape by the processes of cell migration and differential growth rates (morphogenesis).
Up until weeks 26—28 of gestation, the increase in fetal weight is due largely to the accumulation of protein as the major cells of the body are multiplying and enlarging. During the last 10 weeks or so, the fetus starts to accumulate considerable amounts (up to 400 g) of fat, distributed both subcutaneously and deep within the body. Peak velocity of growth in weight of the fetus occurs at around 34 weeks' gestation. The rate of weight gain then declines towards the time of delivery. The exact mechanism for this slowing is not clear but it seems likely that the placental blood supply is less and less able to meet the ever-increasing nutritional demands of the fetus.
A large number of factors may influence the rate of fetal growth but their relative importance remains unclear. Genetic, endocrine, and environmental factors are as important in fetal life as they are in postnatal development, with the genetic constitution setting the upper limits of fetal size, and the level of
23 The control of growth
Fig. 23-1 Fetal and early postnatal growth in boys: (a) increase in length; (b) rate of growth, or growth velocity. In each case the dotted lines represent the theoretical values expected in the absence of any uterine restrictions. In reality, growth commonly slows towards the end of gestation as the placenta becomes less able to meet the ever-growing demands of the fetus. 'Catch-up' growth is seen following delivery, if the child is adequately nourished.
nourishment provided by the placenta determining to what extent the genetic potential is achieved. This, in turn, will be affected by numerous maternal influences such as smoking, medication, alcohol consumption, and nutritional status.
Patterns of growth and development during childhood and adolescence
The rapid rare of growth seen in fetal life continues into the postnatal period but decelerates significantly through early childhood. There is further deceleration leading up to puberty which is
accompanied by the pubertal growth spurt. This pattern is illustrated in Fig. 23.2, which shows the oldest known longitudinal record of growth, carried out during the years 1759 to 1777.
The age at which the adolescent growth spurt takes place varies considerably between individuals. It occurs on average between 10.5 and 13 years in girls and between 12.5 and 15 years in boys. In general, the earlier the growth spurt occurs, the shorter will be the final stature. During this period there is considerable variation in both stature and development between individuals of the same chronological age. The endocrine changes that accompany and may contribute to the adolescent growth spurt will be considered further in Secrion 23.5.
Most body measurements follow approximarely the growth curves described for height. The skeleton and muscles grow in this manner as do many internal organs such as the liver, spleen, and kidneys. Certain tissues, however, do not conform to this pattern and vary in their rate and timing of growth (Fig. 23-3). Examples include the reproductive organs (which show a significant growth spurt during puberty), the brain and skull, and the lymphoid tissue. The brain, together with the skull, eyes and ears, develops earlier than any other part of the body and thus has a characteristic postnatal, curve. The lymphoid tissue also shows a characteristic pattern of growth. It reaches its maximum mass before adolescence and then, probably under the influence of the sex hormones, declines to its adult value. In particular, the thymus gland, which is a well-developed structure in children, is no more than a residual nodule of tissue in adults.
Growth, even of the skeleton, does not cease entirely at the end of the adolescent period. Although there is no further increase in the length of the limb bones, the vertebral column continues to grow until the age of about 30, by the addition of bone to the upper and lower surfaces of the vertebral bodies. This gives rise to an additional height increase of 3—5 mm in the post-adolescent period. However, for practical purposes it may be considered that the average boy stops growing at around 17.5 years of age and the average girl at around 15.5 years of age with a 2-year variability range on either side.
1. Growth occurs at the level of the cells, tissues, and the whole body.
Normal growth is influenced by many factors, genetic and environ
mental. A number of hormones are involved in the regulation
of growth and development, including growth hormone, thyroid
hormones, and sex steroids.
growth in stature ceases. Individual tissues such as the brain and lymphoid tissue show characteristic growth patterns.
23.2 The physiology of bone
Fig. 23.2 (a) and (b) The growth record of an individual child as recorded by his father in the eighteenth century, (c) and (d) A comparison of average growth velocity curves for boys and girls from early childhood to adulthood. Note the timing of the adolescent growth spurts in boys and girls and the difference in final heights achieved.
Bone is a specialized form of connective tissue which is made durable by the deposition of mineral within its infrastructure. In an adult, skeletal bone forms one of the largest masses of tissue, weighing 10—12 kg. Far from being the inert supporting structure that its outward appearance might suggest, bone is a dynamic tissue with a high metabolic activity, which is continuously undergoing complex structural alterations under the influence of mechanical stresses and a variety of hormones. Four main functions are ascribed to bone. These are:
1. the provision of structural support for the body and an attachment for muscles, tendons, and ligaments;
Three major components are found in bone: osteoid, an organic matrix consisting largely of collagen with some hyaluronic acid and chondroitin sulfate; a mineral matrix of calcium phosphate crystals (hydtoxyapatite); and bone cells, including osteoblasts, osteoclasts, osteocytes, and fibroblasts. The process of bone mineralization is not fully understood. Calcium phosphate appears to become oriented along the collagen molecules of the organic matrix. Surface ions of the crystals are hydrated, forming a layer through which exchange of substances with the extracellular medium can occur.
23 The control of growth
Fig. 23.3 Growth curves for individual body tissues.
Fig. 23.4 The structural components of a typical long bone.
The anatomical features of a typical long bone are illustrated in Fig. 23.4. There is a central shaft, or diaphysis, consisting of dense, compact bone, while the regions at each end are called the epiphyses. Between the diaphysis and epiphysis is a region of spongy (cancellous or trabecular) bone, which is the epiphyseal plate or growth plate. Adjacent to this is the growing end of the diaphysis, known as the metaphysis. During growth this region is made of cartilage but once growth is completed following puberty, the plate becomes fully calcified and remains as the epiphyseal line. Growth in length occurs by deposition of new cartilage at the metaphysis and its subsequent mineralization.
The surfaces of the bones are covered by periosteum, which consists of an outer layer of tough fibrous connective tissue and an inner layer of osteogenic ('bone forming') tissue. A central space runs through the center of bones. This is the marrow (or medullary) space which contains the bone marrow and is lined with osteogenic tissue (the endosteum). The marrow spaces of the long bones contain mainly fatty yellow marrow which is not involved in hematopoiesis under normal circumstances. Red marrow is found within the small, flat, and irregular bones of the skeleton, such as the sternum and ilium and it is here that blood cell production is carried out.
Long bones are supplied by three major vessel types: the nutrient artery, periosteal arteries, and the metaphyseal and epiphyseal arteries. The nutrient artery branches from a systemic artery and pierces the diaphysis before giving rise to ascending and descending medullary arteries within the marrow cavity. In turn, these give rise to arteries supplying the endosteum and diaphyses. The periosteal blood supply takes the form of a capillary network, while the metaphyseal and epiphyseal vessels branch off from the nutrient artery. At rest, the arterial flow rate to the skeleton is around 12 per cent of the total cardiac output (2—3 ml 100 mg tissue-1 min-1). The mechanisms that control skeletal circulation are poorly understood, but it is known that blood flow is significantly increased during inflammation and infection and following fracture. The blood flow to the red bone marrow is increased during chronic hypoxia when red blood cell production is enhanced.
The bone cells
Three major cell types are recognized in histological sections of bone: osteoblasts, osteocytes, and osteoclasts. The first two types originate from progenitor cells within the osteogenic tissue of the bone. Osteoclasts are believed to differentiate separately from mononuclear phagocytic cells.
Osteoblasts are present on the surfaces of all bones and line the internal marrow cavities. They secrete the constituents of the organic matrix of bone, including collagen, proteoglycans, and glycoproteins. They are also important in the process of mineralization (calcification) of this matrix.
Osteocytes are mature bone cells derived from osteoblasts which have become trapped in lacunae (small spaces) within the matrix that they have secreted. Adjacent osteocytes are linked by fine cytoplasmic processes that pass through tiny canals between lacunae (canaliculi). This arrangement permits the exchange of calcium from the interior to the exterior of bones and thence into the extracellular fluid. This transfer is known as osteocytic osteolysis and may be used to remove calcium from the most recently formed mineral crystals when plasma calcium levels fall (for more details regarding whole-body calcium balance see Chapter 12).
Osteoclasts are giant multinucleated cells which are believed to arise from the fusion of several precursor cells and therefore contain numerous mitochondria and lysosomes. They are highly mobile cells which are responsible for the resorption of bone
23.3 Bone development and growth
during growth and skeletal remodeling. They are abundant at or near the surfaces of bone undergoing erosion. At their site of contact with the bone is a brush border of microvilli which infiltrates the disintegrating bone surface. Bone dissolution is brought about by the actions of collagenase, lysosomal enzymes, and acid phosphatase. Calcium, phosphate, and the constituents of the bone matrix are released into the extracellular fluid as bone mass is reduced. The activity of the osteoclasts is controlled by a number of hormones, notably parathyroid hormone, calcitonin, thyroxine, estrogens, and the metabolites of vitamin D (see Chapter 12 for further details).
23.3 Bone development and growth (osteogenesis)
At 6 weeks of gestation, the fetal skeleton is constructed entirely of fibrous membranes and hyaline cartilage. From this time, bone tissue begins to develop and eventually replaces most of the existing structures. Although ossification begins early in fetal life, it is not complete until the third decade of adult life. The bones of the cranium, lower jaw, and the clavicles develop from fibrous membranes by a process called intramembranous ossification. In this process new bone is formed on the surface of existing bone. The bones of the rest of the skeleton grow as a result of the replacement of hyaline cartilage templates by bone (a process known as endochondral ossification).
Growth of bone length
A long bone such as the radius in the forearm is laid down first as a cartilage model. At the center of this model, the so-called primary center of ossification, the cartilage cells break down and bone appears. This process begins early in fetal life and, by shortly before birth, secondary centers of ossification have also developed, predominantly at the ends of the bone or epiphyses. The areas of cartilage between the diaphysis and the epiphyses are known as the growth plates. In the part of the growth plate immediately under the epiphysis is a layer of stem cells, or chon-droblasts. These give rise to clones of cells (chondrocytes)
arranged in columns extending inwards from the epiphysis towards the diaphysis.
Several zones may be distinguished within the columns of chondrocytes. The outer zone is one of proliferation in which the cells are dividing rapidly. Beneath this are layers in which the cells mature, enlarge, and eventually degenerate, as shown in Fig. 23.5. The innermost layer of cells is the region of calcification. Here, the osteogenic cells differentiate into osteoblasts and lay down bone. In a radiograph of a rapidly growing bone the zone adjacent to the main shaft is clearly seen as a region of high density because here calcium, which is opaque to the X rays, is being laid down at maximal concentration.
Thus, at one end of the epiphyseal plate, cartilage is produced, while at the other end it is degenerating. Growth in length is therefore dependent upon the proliferation of new cartilage cells. In humans it takes around 20 days for a cartilage cell to complete the journey from the start of proliferation to degeneration. Clearly, the bone marrow cavity must also increase in size as the bone grows, and to ensure this, osteoclasts erode bone within the diaphysis.
At the end of the growth period, the growth plate thins as it is gradually replaced by bone until it is eliminated altogether and the epiphysis and diaphysis are unified, a process known as synostosis. Following this 'fusion' of the epiphyseal plate, no further increase in bone length is possible at this site. Although growth in length of most bones is complete by the age of 20 (see later sections) the clavicles do not ossify completely until the third decade of life. The dates of ossification are fairly constant between individuals but different between bones. This fact is exploited in forensic science to determine the age of a body according to which bones have and have not ossified.
Growth of bone diameter
Like the bones of the skull and face, the growth in width of long bones is achieved by intramembranous ossification. Cells within the osteogenic tissue multiply to lay down new bone on the outside of the existing bone. Rapid ossification of this new membranous bone takes place to keep pace with the growth in length of the bone.
Remodeling of bone
Even after growth has ended, the skeleton is in a continuous state of remodeling as it is renewed and revitalized at the tissue level. Large volumes of bone are removed and replaced and bone architecture continually changes as 5—7 per cent of bone mass is recycled each week. Furthermore, following a break to a bone, self-repair takes place remarkably quickly. Remodeling allows bone to adapt to external stresses, adjusting its formation to increase strength when necessary. Remodeling occurs in cycles of activity in which resorption precedes formation. Osteoclastic activity, through which bone is eroded, is followed by a period of intense osteoblastic activity, in which new bone is laid down to replace it.
23 The control of growth
Fig. 23-5 A diagrammatic representation of long bone growth, showing the junction between the epiphysis and the diaphysis (bone shaft). New cells formed in the proliferative region move down to the hypertrophic region to add to bone accumulating on the top of the diaphysis.
In general terms, bone is deposited in proportion to the load it must bear. It follows therefore that in an immobilized person bone mass is rapidly (though reversibly) lost, a process known as disuse osteoporosis. Astronauts experiencing prolonged periods of weightlessness in space, have been shown to lose up to 20 per cent of their bone mass in the absence of properly planned exercise programs. The factors that control the rate of deposition and loss of bone in response to mechanical requirements, however, remain largely unknown.
23.4 The role of growth hormone (somatotropin) in the control of growth
Growth is the result of the multiple interactions of circulating hormones, tissue responsiveness, and the supply of nutrients and energy for growing tissues. Many hormones are known to be involved in the regulation of growth, at different stages of life. Nevertheless, the hormone that undoubtedly exerts a dominant effect on normally coordinated growth is growth hormone.
The nature and secretion of growth hormone (GH) has been discussed fully in Secrion 12.3, but a brief summary may be helpful here. GH is a polypeptide (Mt 22 000) derived from the pituitary somatotrophs. It bears a marked structural similarity to prolactin and human placental lactogen. The secretion of GH is controlled by hypothalamic releasing hormones. GHRH (growth hormone-releasing hormone) stimulates the output of GH while somatostatin inhibits it. GH shows a marked irregular pulsatile pattern of release which is influenced by a number of physiological stimuli. Stress and exercise, for example, borh stimulate GH secretion, while there is a significant increase in the rate of secretion during slow-wave sleep, particularly in children. Both the pulsatile character and the sleep-induced patterns of release are lost in patients suffering from hypo- or hypersecretion of GH (Fig. 23.6).
Other hormones and products of metabolism also influence the rate of GH secretion. Estrogens, for example, increase the
23.4 The role of growth hormone in the control of growth
Fig. 23-6 A comparison of the pattern of secretion of GH in normal individuals and in patients suffering from acromegaly (GH excess in adulthood) and GH deficiency. Note that in each of the abnormal states, pulsatile secretion is lost. In acromegaly there is a sustained high circulating level of GH.
sensitivity of the pituitary to GHRH, an effect that contributes to the earlier growth spurt seen in adolescent girls compared with boys. GH secretion is decreased by the adrenal glucocorticoid hormones and stimulated by insulin. Oral glucose depresses GH release while secretion is promoted by low levels of plasma glucose.
In common with most endocrine systems, the secretion of GH is under negative feedback control. This is believed to be mediated both by GH itself (chiefly at the level of the hypothalamus) and by the insulin-like growth factors (IGFs—see below), which are thought to act at both pituitary and hypothalamic levels. GH interacts with its target cells at the plasma membrane, where it binds to surface receptors. Synthesis of these receptors requires the presence of GH itself, while an excess of GH causes down-regulation of the receptors. The mechanisms of signal transduction have recently been clarified. GH activates membrane-bound tyrosine kinases which phosphorylate a group of proteins that activate gene transcription.
The actions of GH may be divided into metabolic and growth-promoting effects. The metabolic actions of GH tend to oppose those of insulin and are largely direct in nature. GH exerts its direct actions on a variety of target tissues, principally liver, muscle, and fat. It depresses glucose metabolism (to spare glucose for use by the CNS in times of fasting or starvation) and stimulates lipolysis and the uptake of amino acids into cells for protein synthesis.
The growth-promoting actions of GH embrace both direct and indirect effects. GH seems to exert a direct stimulatory effect on chondrocytes, increasing the rate of differentiation of these cells and, therefore of cartilage formation. Many of the direct metabolic actions of GH, such as the increase in uptake of amino acids and the rate of protein synthesis, will also contribute to the overall processes of growth and repair.
The indirect actions of growth hormone are mediated by a family of peptide hormone intermediaries called insulin-like growth factors (IGFs) formerly known as somatomedins. They have a molecular weight of around 7000 and are structurally related to proinsulin, the precursor to insulin. The IGFs are syn-
thesized in direct response to GH, chiefly by the liver but also by other tissues, including cartilage and fat. Plasma IGF-1 is increased by administration of GH, with a time-lag of 12—18 hours, and is reduced in individuals who lack GH. IGFs have plasma half-lives in excess of that of GH because they are carried in the blood bound to several proteins. The blood level of IGF-1 is low in infancy, rises gradually until puberty, then increases more swiftly to reach a peak that coincides with the peak height increase (see Fig. 23.2) after which it falls to its adult (and pre-pubertal) value.
The actions of the IGFs, as their name suggests, tend to be insulin-like in character and account principally for the growth-promoting effects of GH. They act on cartilage, muscle, fat, fibroblasts, and tumor cells. More specifically related to bone growth, is the action of IGFs (particularly IGF-1 and IGF-2) in stimulating the clonal expansion of chondrocytes and the formation and maturation of osteoblasts in the growth plate. All aspects of the functions of the chondrocytes are stimulated, including the incorporation of the amino acid proline into collagen and its subsequent conversion to hydroxyproline. Furthermore, GH (via IGFs) stimulates the incorporation of sulfate into chondroitin. Chondroitin sulfate and collagen, together, form the tough inorganic matrix of cartilage. Growth of soft tissue and the viscera is also attributed to the indirect actions of GH via the IGFs.
A summary of the direct and indirect actions of GH, and of the factors regulating GH output is shown in Fig. 23.7.
The importance of GH in growth at different stages of life
Figure 23.8 illustrates the pattern of GH secretion throughout life. During the fetal period, GH itself is of little importance in the control of growth and GH receptors do not appear until the final 2 months of gestation. However, the growth factors IGF-1 and IGF-2 appear to play a dominant role in fetal growth.
Following delivery, and in the early part of childhood, GH secretion increases considerably, and during this phase overall
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