IGF-1 regulation of key signaling pathways in bone

Abstract

Insulin-like growth factor 1 (IGF-1) is an unique peptide that functions in an endocrine/paracrine and autocrine manner in most tissues. Although it was postulated initially that liver-derived IGF-1 was the major source of IGF-1 (that is, the somatomedin hypothesis), it is also produced in a wide variety of tissues and can function in numerous ways as both a proliferative and differentiative factor. One such tissue is bone and all cell lineages in the skeleton have been shown to not only require IGF-1 for normal development and function but also to respond to IGF-1 via the IGF-1 receptor. Ligand-receptor activation leads to several distinct downstream signaling cascades, which have significant implications for cell survival, protein synthesis and energy utilization. The novel role of IGF-1 in regulating metabolic demands of the bone remodeling unit is currently under investigation. More studies are likely to shed new light on various aspects of skeletal physiology and potentially may lead to new therapeutics.

Figure 1

The figure represents a cartoon depicting the key signaling pathways that have been discussed in this review. IGF-1 can activate MAPK and PI3K signaling, as we have concentrated on AKT signaling in this review, the figure illustrates functions of AKT on its downstream targets in detail. The functions of IGF-1 on mitochondrial metabolism during chondrocyte and osteoblast differentiation and the role of IGF-1 on glucose metabolism have not been completely elucidated yet. There is some data showing that mTORC2 can activate the Warburg effect during Wnt-induced osteoblast differentiation. The functions of mTORC1 through activation of S6K and inhibition of 4EBP and the role of mTOR on oxidative phosphorylation and glycolysis should be studied further. PDK1, 3-phosphoinositide-dependent protein kinase-1.