Abstract
Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with recombinant IGF-1 in both children and animals are few. Here, we used two novel transgenic mouse strains to test the long-term effects of elevated circulating IGF-1 on body size and skeletal development. Overexpression of the rat igf1 transgene in livers of mice with otherwise normal IGF-1 expression (HIT mice) resulted in approximately threefold increases in serum IGF-1 levels throughout growth, as well as greater body mass and enhanced skeletal size, architecture, and mechanical properties. When the igf1 transgene was overexpressed in livers of igf1 null mice (KO-HIT), the comparably elevated serum IGF-1 failed to overcome growth and skeletal deficiencies during neonatal and early postnatal growth. However, between 4 and 16 weeks of age, increased serum IGF-1 fully compensated for the absence of locally produced IGF-1 because body weights and lengths of KO-HIT mice became comparable with controls. Furthermore, micro-computed tomography (µCT) analysis revealed that early deficits in skeletal structure of KO-HIT mice were restored to control levels by adulthood. Our data indicate that in the absence of tissue igf1 gene expression, maintaining long-term elevations in serum IGF-1 is sufficient to establish normal body size, body composition, and both skeletal architecture and mechanical function. © 2010 American Society for Bone and Mineral Research.
Highlights
The growth hormone (GH)–insulin-like growth factor 1 (IGF-1) axis is notably complex owing to the number of IGF-1binding proteins that modulate its activities,(1) the ability of GH and IGF-1 to act individually as well as collectively, and in particular, the ability of IGF-1 to act via both endocrine and autocrine/paracrine pathways.[2,3,4] As an endocrine agent, IGF-1 is the major circulating hormone produced by the liver, principally in response to GH; as a paracrine factor, IGF-1 is produced by a wide range of cell types, where its expression is regulated by GH and by numerous other local and systemic agents.This complexity of the GH–IGF-1 system is especially evident in its control of skeletal development
In liver-IGF-1-deficient (LID) mice, which Exhibit 75% reductions in serum IGF-1 but normal skeletal IGF-1 expression, serum IGF-1 regulates periosteal bone growth and determines bone size and bone strength.[10] we found that decreases in endocrine IGF1 levels impair skeletal development only at the onset of puberty.[10]. We proposed that endocrine IGF-1 is a major determinant of skeletal growth at prepubertal age and during puberty, whereas autocrine/paracrine IGF-1 regulates skeletal growth early pre- and postnatally
It is important to note that serum IGF-1 levels did not differ between mice that carry one or two sets of the igf1 transgene, but we present only homozygous transgenic mice
Summary
The growth hormone (GH)–insulin-like growth factor 1 (IGF-1) axis is notably complex owing to the number of IGF-1binding proteins that modulate its activities,(1) the ability of GH and IGF-1 to act individually as well as collectively, and in particular, the ability of IGF-1 to act via both endocrine and autocrine/paracrine pathways.[2,3,4] As an endocrine agent, IGF-1 is the major circulating hormone produced by the liver, principally in response to GH; as a paracrine factor, IGF-1 is produced by a wide range of cell types, where its expression is regulated by GH and by numerous other local and systemic agents This complexity of the GH–IGF-1 system is especially evident in its control of skeletal development. We performed longitudinal analyses of three mouse models: [1] control mice, which express normal levels of tissue and serum IGF-1, [2] hepatic igf transgenic (HIT) mice, which express normal levels of tissue IGF-1 but overexpress the rat igf transgene in liver and have increased serum IGF-1 levels, and [3] mice with the igf gene totally ablated but overexpressing the rat igf transgene in liver (KO-HIT), exhibiting increased serum IGF-1 levels in the absence of igf gene expression in tissues.[17]
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