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. Ligandreceptor 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.

Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis

“…Osteoblasts express the IGF1 receptor (IGF1R) and secrete IGF1 into the microenvironment. In these cells, IGF1R mutations and IGF1 overexpression are found to correlate with skeletal and craniofacial defects Guntur and Rosen, 2013). A lack of IGF1 and IGF1R in mutant mice results in severe retardation in bone development, hypomineralized skeletons and growth plate defects (Woods et al, 1996;Bikle et al, 2001).…”

“…In vivo, IGF1 signaling stimulates osteoblast survival, proliferation, differentiation and matrix production (Bodine et al, 2007;Guntur and Rosen, 2013). Osteoblasts express the IGF1 receptor (IGF1R) and secrete IGF1 into the microenvironment.…”

Whey Protein Supplementation and Higher Total Protein Intake Do Not Influence Bone Quantity in Overweight and Obese Adults Following a 36-Week Exercise and Diet Intervention

“…Kininogen fragment 1.2 and cystatin C are considered the anabolic components of MBP, causing a stimulation of bone formation and a suppression of bone resorption (44,46,48,50). In addition to MBP and its anabolic effects on bone, WP is also shown to increase serum insulin-like growth factor I (IGF-I) concentrations (50,51), a hormone important in osteoblast differentiation (52). These inherent properties of WP highlight the differential effects of protein source on bone and suggest potential therapeutic effects.…”

The Use of Molecular Pathway Inhibitors in the Treatment of Osteosarcoma

“…The PI3K/Akt pathway is implicated in the proliferation and invasion of malignant OS via multiple pathways, such as increasing the expression of cyclins and cyclin-dependent kinases that act as positive regulators of the cell cycle in OS [74]. The mammalian target of rapamycin (mTOR) is one of the most important downstream efectors of PI3K/Akt and controls cell cycling and protein synthesis by activation of its downstream targets p70S6K and 4E-BP [68].…”

“…This autophosphorylation leads to the downstream activation of insulin receptor substrate (IRS) proteins and Shc, an adapter protein between IGF-IR and the network of their signaling pathways [67,68] (Figure 2). Phosphorylation of Shc and its binding to Grb2 is required for the activation of mitogen-activated protein kinases (MAPK)/extracellular-signal-regulated kinases (ERK), both important regulators of proliferation, invasion, angiogenesis, and inlammatory responses [69,70].…”