Insulin-like growth factor-I and bone: lessons from mice and men
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REVIEW
Insulin-like growth factor-I and bone: lessons from mice and men Masanobu Kawai & Clifford J. Rosen
Received: 19 August 2008 / Revised: 29 September 2008 / Accepted: 6 October 2008 / Published online: 15 November 2008 # IPNA 2008
Abstract Studies of humans and animals have illustrated a strong association between insulin-like growth factor (IGF)I and skeletal acquisition. However, the precise molecular and cellular mechanisms underlying this effect still largely remain unknown. Recent advances in molecular and genetic techniques for in vivo studies provide excellent tools for us to explore how circulating and skeletal insulin-like growth factor-I (IGF-I) may affect not only peak bone mass but also bone loss. This review highlights recent findings that shed new light on the interaction of the IGF-I signaling pathway with other skeletal networks, and the role of IGF-I in the bone marrow milieu.
in vitro models, and signaling pathways for this peptide have become firmly established. However, the relative contribution of circulating and skeletally produced IGF-I in bone turnover remains unclear. The recent emergence of molecular and genetic techniques for in vivo studies provides an excellent tool to for us explore these issues. In this review, we will discuss the role of circulating and skeletal IGF-I in bone acquisition and the effects of IGF-I treatment on bone mass.
Keywords Insulin-like growth factor-I . Skeletal acquisition
The IGF-I regulatory system is composed of IGF-I, IGF-I receptor I (IGF1R), and regulatory proteins, including IGFbinding proteins (IGFBPs) 1–6 and the acid-labile subunit (ALS) [3]. IGF-I is a single-chain polypeptide and consists of 70 amino-acid residues. The distribution of IGF-I in serum and skeletal environment is an important component in IGF-I action, and it is determined by the relative saturation by IGFBPs. This family of proteins can act as agonists for IGF-I or can block the actions of IGF-I by preventing access to the IGF1R. The redundancy exerted by the IGFBPs in the IGF regulatory system provides an additional level of regulation and can be utilized to deliver IGF-I in an endocrine fashion. IGF-I exerts its action by binding to the IGF-I receptor, which induces receptor autophosphorylation in the intracellular kinase domain. Upon receptor activation, a number of protein substrates, including insulin receptor substrate-1 (IRS1) and Src homology and collagen protein (SHC), are activated and transduce multiple signaling pathways, including the PI3K/PDK-1/Akt pathway and the Ras/Raf-1/MAPK pathway. IRS-1 interacts with PI3K, and activation of PI3K catalyzes phosphorylation of phosphatidylinositol-4,
Introduction Salmon and Daughaday discovered the presence of a soluble factor induced by growth hormone that had insulin-like properties approximately 50 years ago; subsequently, this factor was identified as insulin-like growth factor-I (IGF-I) [1]. Since then, numerous discoveries have enriched our understanding of this peptide, especially in respect to its role in bone rem
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