ABSTRACT
I. Introduction: The Role of Insulin-Like Growth Factors in Bone Disease .......................................................................... 186
II. Overview of the IGFs and the IGF Regulatory System with Particular Focus on the Skeleton........................................... 187 A. Circulating IGFs and their Regulation ......................... 187 B. Skeletal IGFs, IGFBPs, and Their Roles in Bone
Turnover......................................................................... 189
III. Application of the IGFs to Skeletal Disorders in Animals .............................................................................. 192 A. General Principles of Targeting Skeletal IGFs ............. 192 B. Types of Administration and Experimental Models.... 192
IV. Human Studies with rhIGF-I................................................. 197 A. Introduction ................................................................... 197 B. Studies with rhIGF-I ...................................................... 197 C. Studies with rhGH and/or rhIGF-I .............................. 199 D. Conclusions Concerning the Use of rhIGF-I
in Humans...................................................................... 200
V. Future Prospects ........................................................................... 201
Acknowledgment ............................................................................. 201
References ......................................................................................... 201
Insulin-like growth factors (previously called somatomedins) are ubiquitous polypeptides produced, secreted, and degraded by various tissues.1 In mammalian species, IGF-I and IGF-II are found in large concentrations bound to a family of IGF-specific binding proteins (IGFBPs). Because they circulate in the blood, the IGFs have traditionally been considered endocrine “effectors” performing two distinct physiologic roles: 1) mediating growth hormone’s activity on the cartilaginous growth plate (hence the term somatomedins), and 2) exerting insulin-like action on target cells (hence the name insulin-like growth factors). IGF-I is essential for linear bone growth. This is best illustrated by single point mutations in the growth hormone receptor gene which result in a short stature phenotype despite high levels of circulating growth hormone (GH).2 Also, it is clear that under specific circumstances, IGFs can lower serum glucose and act directly on the insulin receptor. But the IGFs also have potent paracrine and autocrine effects on cell growth and differentiation that are independent of GH. It is this fine balance between local and systemic activities of these unique growth factors that permit their consideration as possible treatment options for several metabolic disorders.
