I I GH-insensitive + IGF-I H GH-deficient + GH

i i before treatment first year second year third year

FIGURE 4 Insulin-like growth factor-I (IGF-I) treatment of children with growth hormone (GH) receptor deficiency compared to GH treatment of children with GH deficiency. (Plotted from data of Guevara-Aguirre J, Rosenbloom AL, Vasconez O, Martinez V, Gargosky S, Allen L, Rosenfeld R, J Clin Endocrinol Metab 1997; 82:629-633.)

concentrations of GH in their blood. Daily treatment with even large doses of GH does not accelerate their growth. Similarly, a child with a homozygous deletion of the IGF-I gene suffered severe pre- and postnatal growth retardation that was partially corrected by daily treatment with IGF-I.

While overwhelming evidence indicates that IGF-I stimulates cell division in cartilage and many other tissues and accounts for much and perhaps all of the growth-promoting action of GH, the somatomedin hypothesis as originally formulated is inconsistent with some experimental findings. Production of IGF-I is not limited to the liver and may be increased by GH in many tissues, including cells in the epiphyseal growth plate. Direct infusion of small amounts of GH into epiphyseal cartilage of the proximal tibia in one leg of hypophy-sectomized rats was found to stimulate tibial growth of that limb, but not of the contralateral limb. Only a direct action of GH on osteogenesis can explain such localized stimulation of growth, because IGF-I that arises in the liver is equally available in the blood supply to both hind limbs. It is now apparent that GH stimulates prechondrocytes and other cells in the epiphyseal plates to synthesize and secrete IGFs that act locally in an autocrine or paracrine manner to stimulate cell division, chondrocyte maturation, and bone growth. Evidence to support this conclusion includes findings of receptors for both GH and IGF-I in cells in the epiphyseal plates along with the GH-dependent increase in mRNA for IGFs. Thus, growth of the long bones might be stimulated by IGF-I that reaches them either through the circulation or by diffusion from local sites of production, or some combination of the two. The failure of the original experiments to demonstrate these actions may be attributable to deficiencies in the culture conditions.

A genetic engineering approach was adopted to evaluate the relative importance of locally produced and bloodborne IGF-I. A line of mice was developed in which the IGF-I gene was selectively disrupted only in hepatocytes. Concentrations of IGF-I in the blood of these animals were severely reduced, but their growth and body proportions were no different from those of control animals that produced normal amounts of IGF-I in their livers; however, even though the lengths of their limb bones were normal, the diameters of these bones were smaller than normal. These findings indicate that locally produced IGF-I is sufficient to account for normal growth at the epiphyses, but that IGF-I in the circulation is important for circumferential growth, primarily of cortical bone. In addition, the average concentration of GH in the blood of these genetically altered mice was considerably increased. This finding is consistent with findings that IGF-I exerts a negative feedback effect on GH secretion. The current view of the

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