Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r)

GH and IGF-I are important regulators of bone homeostasis and are central to the achievement of normal longitudinal bone growth and bone mass. Although GH may act directly on skeletal cells, most of its effects are mediated by IGF-I, which is present in the systemic circulation and is synthesized by peripheral tissues. The availability of IGF-I is regulated by IGF binding proteins. IGF-I enhances the differentiated function of the osteoblast and bone formation. Adult GH deficiency causes low bone turnover osteoporosis with high risk of vertebral and nonvertebral fractures, and the low bone mass can be partially reversed by GH replacement. Acromegaly is characterized by high bone turnover, which can lead to bone loss and vertebral fractures, particularly in patients with coexistent hypogonadism. GH and IGF-I secretion are decreased in aging individuals, and abnormalities in the GH/IGF-I axis play a role in the pathogenesis of the osteoporosis of anorexia nervosa and after glucocorticoid exposure.

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Growth Hormone, Insulin-Like Growth Factors, and the Skeleton

Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer.

Publisher Summary This chapter focuses on the role of the insulin-like growth factor system in human cancer. The normal process of growth and differentiation results from the genetically programmed action of a number of different cellular and extracellular factors. Derangement in the function of one or more of those agents can result in a pathologic phenotype, including neoplastic growth. A family of growth factors shown to be intimately involved in the regulation of cell growth as well as in cellular transformation is the insulin-like growth factor (IGF) family. IGF-I and IGF-II are mitogenic polypeptides produced in the largest amounts by the liver and secreted into the circulation, where they mediate the effects of growth hormone (GH) on longitudinal growth. In addition to ligands and receptors, the IGF system comprises a third category of molecules, which bind IGFs in the circulation and in extracellular compartments. Six IGF-binding proteins (IGFBPs) have been characterized to date. Binding of IGFs to the IGF-I receptor induces receptor autophosphorylation. The cell cycle consists of four major phases: (1) the presynthetic phase, G; (2) the phase of DNA synthesis, S; (3) the premitotic phase, G; and (4) mitosis, M. IGF-I, IGF-II, and insulin are chemotactic agents for the human melanoma cell line A2058, as assayed in a modified Boyden chamber. The chapter also gives selected examples of IGF involvement in human cancer. The wealth of information generated in the IGF field, as well as continued research efforts, both basic and clinic, promise to produce rational therapeutic approaches for those cancers in which the IGF system is involved.

The Role of the Insulin-like Growth Factor System in Human Cancer

Bone Cells and their Function Bone Matrix Biology of Growth Factors Mechanisms of Action of Skeletal Growth Factors in Osteoblasts In Vitro and In Vivo Models to Study Growth Factor Actions in Bone Insulin-like Growth Factors: Their Binding Proteins and Growth Regulation Insulin-like Growth Factors and the Skeleton Clinical Aspects of Insulin-like Growth Factors Biology of Platelet-Derived Growth Factor Platelet-Derived Growth Factor: Skeletal Actions and Regulation Fibroblast Growth Factors and their Receptors Fibroblast Growth Factors and Osteogenesis Fibroblast Growth Factors, Chondrogenesis, and Related Clinical Disorders Hepatocyte Growth Factor Transforming Growth Factor-B Transforming Growth Factor-B in Skeletal Development and Maintenance Activin and Follistatin Activin, Follistatin, and Bone Bone Morphogenetic Proteins Bone Morphogenetic Proteins and Skeletal and Nonskeletal Development Bone Morphogenetic Proteins and the Adult Skeleton The Role of Growth Factors in Fracture Healing Clinical Disorders Associated with Bone Morphogenetic Proteins Parathyroid Hormone-related Protein Role of Parathyroid Hormone-related Protein and Indian Hedgehog in Skeletal Development Osteoprotegerin Nonskeletal Effects of Cytokines Secreted by Bone Cells Colony-Stimulating Factors and Bone Role of Cytokines in Postmenopausal Osteoporosis Role of Cytokines in Osteopetrosis Cytokines, Growth Factors, and Malignancy Clinical Use of Growth Factors Use of Growth Factors for Osteoporotic Therapy Inde

Skeletal Growth Factors

Insulin-like growth factor I (IGF-I) mediates many of the systemic growth-promoting effects of growth hormone and also functions as a locally acting growth stimulator. In mammals, IGF-I ge...

Yoshitaka Kajimoto

Papers

Functional analysis of the rat insulin-like growth factor I gene and identification of an IGF-I gene promoter.