IBMS BoneKEy | Perspective

Insulin-like growth factor-I and bone

Daniel D Bikle
Yongmei Wang

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DOI:10.1138/20110521

Abstract

Insulin-like growth factor-I (IGF-I) is produced by chondrocytes, osteoblasts, osteocytes, and osteoclasts, and its receptor (IGF-IR) is found in all of these cells. The actions of IGF-I are mediated by IGF-IR, a tetrameric membrane-bound receptor homologous to the insulin receptor. When activated this receptor sets into motion two signaling pathways, the PI3K/Akt pathway and the Ras/Raf/MAPK/ERK pathway. Skeletal loading in vivo or of osteoblasts and osteocytes in vitro enhances IGF-I signaling by inducing IGF-I production and stimulating the interaction between IGF-IR and selected integrins that are critical for IGF-I signaling. The actions of IGF-I are regulated by the six IGF-binding proteins in both an inhibitory and stimulatory fashion. Different binding proteins have different actions often depending on the context of the experimental situation. The relative contributions of circulating IGF-I (produced primarily in the liver) and that produced by bone remain in dispute, although both are involved in skeletal development. Cell-specific deletion of IGF-IR blunts chondrocyte and osteoblast proliferation and differentiation and inhibits osteoclastogenesis. IGF-I facilitates the skeletal actions of a number of calciotropic hormones including parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), growth hormone (GH), thyroid hormone, and glucocorticoids, and regulates the production of PTHrP and GH. Thus through numerous means IGF-I plays a key role in all aspects of skeletal development, the skeleton's subsequent remodeling, and its response to hormonal and environmental factors. This Perspective focuses on the role of IGF-I and IGF-IR in the regulation of skeletal growth and remodeling.

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