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bony epiphysis epiphyseal growth plate diaphysis bony epiphysis epiphyseal growth plate diaphysis

j] germinal zone proliferative zone hypertrophic zone calcifying zone

FIGURE 3 Schematic representation of the tibial epiphyseal growth plate. (FromOhlssonC, Isgaard J, Tornell J, Nilsson A, Isaksson OGP, Lindahl A., Acta Paediatr 1993; 381(suppl.):33-40. With permission.)

j] germinal zone proliferative zone hypertrophic zone calcifying zone

FIGURE 3 Schematic representation of the tibial epiphyseal growth plate. (FromOhlssonC, Isgaard J, Tornell J, Nilsson A, Isaksson OGP, Lindahl A., Acta Paediatr 1993; 381(suppl.):33-40. With permission.)

particular, the vertebral column and long bones of the legs. Growth of these bones occurs by a process called endochondral ossification, in which proliferating cartilage is replaced by bone. The ends of long bones are called epiphyses and arise from ossification centers that are separate from those responsible for ossification of the diaphysis, or shaft. In the growing individual, the epiphyses are separated from the diaphysis by cartilaginous regions called epiphyseal plates, in which continuous production of chondrocytes provides the impetus for diaphyseal elongation. Chondrocytes in epiphyseal growth plates are arranged in orderly columns in parallel with the long axis of the bone (Fig. 3). Frequent division of small, flattened cells in the germinal zone at the distal end of the growth plate provides for continual elongation of columns of chondrocytes. As they grow and mature, chondrocytes produce the mucopolysac-charides and collagen that constitute the cartilage matrix. Cartilage cells hypertrophy, become heavily vacuolated, and degenerate as the surrounding matrix becomes calcified. Ingrowth of blood vessels and migration of osteoblast progenitors from the marrow result in replacement of calcified cartilage with true bone. Proliferation of chondrocytes at the epiphyseal border of the growth plate is balanced by cellular degeneration at the diaphyseal end, so in the normally growing individual the thickness of the growth plate remains constant as the epiphyses are pushed further and further outward by the elongating shaft of bone. Eventually, progenitors of chondrocytes are either exhausted or lose their capacity to divide. As remaining chondrocytes go through their cycle of growth and degeneration, the epiphyseal plate becomes progressively narrower and is ultimately obliterated when diaphyseal bone fuses with the bony epiphyses. At this time, the epiphyseal plates are said to be closed, and the capacity for further growth is lost. In the absence of GH there is severe atrophy of the epiphyseal plates, which become narrow as proliferation of cartilage progenitor cells slows markedly. Conversely, after GH is given to a hypopituitary subject, resumption of cellular proliferation causes columns of chondrocytes to elongate and epiphyseal plates to widen.

Growth of bone requires that diameter as well as length increase. Thickening of long bones is accomplished by proliferation of osteoblastic progenitors from the connective tissue sheath (periosteum) that surrounds the diaphysis. As it grows, bone is also subject to continual reabsorption and reorganization, with the incorporation of new cells that originate in both the periosteal and endosteal regions. Remodeling, which is an intrinsic property of skeletal growth, is accompanied by destruction and replacement of calcified matrix, as described in Chapter 43. Treatment with GH often produces a transient increase in urinary excretion of calcium and phosphorus, reflecting bone remodeling. Increased urinary hydroxyproline derives from breakdown and replacement of collagen in bone matrix.

The Somatomedin Hypothesis

The epiphyseal growth plates are obviously stimulated after GH is given to hypophysectomized animals, but little or no stimulation of cell division, protein synthesis, or incorporation of radioactive sulfur into mucopolysaccharides of cartilage matrix was observed in early experiments in which epiphyseal cartilage was taken from hypophysectomized rats and incubated with GH. In contrast, when cartilage taken from the same rats was incubated with blood plasma from hypophy-sectomized rats that had been treated with GH, there was a sharp increase in matrix formation, protein synthesis, and DNA synthesis. Blood plasma from normal rats produced similar effects, but plasma from hypophysectomized rats that had not been given GH had little effect. These experiments gave rise to the hypothesis that GH may not act directly to promote growth but, instead, stimulates the liver to produce an intermediate, bloodborne substance that activates chon-drogenesis and perhaps other GH-dependent growth processes in other tissues. This substance was later named somatomedin (somatotropin mediator) and, upon subsequent purification, was found to consist of two closely related substances that also produce the insulinlike activity that persists in plasma after all the authentic insulin is removed by immunoprecipitation. These substances are now called insulin-like growth factors, or IGF-I and IGF-II. Of the two, IGF-I appears to be the more important mediator of the actions of GH and has been studied more thoroughly. Although some aspects of the original somatomedin hypothesis have been discarded (see below), the crucial role of IGF-I as an intermediary in the growth promoting action of GH is now firmly established.

In general, plasma concentrations of IGF-I reflect the availability of GH or the rate of growth. They are higher than normal in blood of persons suffering from acrome-galy and are very low in GH-deficient individuals. Children whose growth rate is higher than average have higher than average concentrations of IGF-I, while children at the lower extreme of normal growth have lower values. When GH is injected into GH-deficient patients or experimental animals, IGF-I concentrations increase after a delay of about 6 to 8 hours and remain elevated for more than a day. Children or adults who are resistant to GH because of a receptor defect have low concentrations of IGF-I in their blood despite high concentrations of GH. Growth of these children is restored to nearly normal rates following daily administration of IGF-I (Fig. 4). Disruption of the IGF-I gene in mice causes severe growth retardation despite high

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