Regulation of Insulin-Like Growth Factor-I (IGF-I) Delivery by IGF Binding Proteins and Receptors
Department of Chemical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA. Annals of Biomedical Engineering
(Impact Factor: 3.2).
05/2006; 34(4):618-32. DOI: 10.1007/s10439-005-9064-6
Delivery of growth factors via the bloodstream for the treatment of various diseases is regulated in part by interactions with cell surface binding elements. Understanding the kinetics of growth factor binding and transport by cells would, therefore, be advantageous. This report quantifies the binding, internalization, and transport of insulin-like growth factor-I (IGF-I) across bovine aortic endothelial cells (BAEC) cultured in vitro. Binding analysis indicated that IGF binding proteins (IGFBPs), primarily localized with the extracellular matrix, were the primary IGF-I binding elements in our system, with twice as many binding sites (8.0 +/- 1.9 x 10(4) per cell) as IGF-I receptors (IGF-IR) (3.9 +/- 0.6 x 10(4) per cell). Internalization of IGF-I by IGF-IR, but not IGFBPs, was detected, however both receptor and IGFBP binding were shown to inhibit rather than enhance the transport of intact IGF-I, albeit in different ways. IGFBPs retained IGF-I in the apical region while IGF-IR binding led to protein degradation. Based on our computational modeling and experimental data, we hypothesize that IGFBPs could function as a reservoir for IGF-I, sequestering it for later release and transport, and that this reservoir function of the IGFBPs could be used to promote controlled localized delivery of IGF-I.
Available from: Moataz Eltoukhy
- "Subsequently, it is shown how this formulation is integrated into the framework of the mechano-electrochemical mixture theory. 3.1 IGF-1 interaction with ECM When trafficking in the ECM of cartilage, IGF-1 competitively interacts with matrix-associated BPs and CSRs (Paye and Forsten-Williams 2006). Interaction with BPs solely results into a reversible binding reaction. "
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ABSTRACT: The production of extracellular matrix (ECM) components of articular cartilage is regulated, among other factors, by an intercellular signaling mechanism mediated by the interaction of cell surface receptors (CSR) with insulin-like growth factor-1 (IGF-1). In ECM, the presence of binding proteins (IGFBP) hinders IGF-1 delivery to CSR. It has been reported that levels of IGF-1 and IGFBP in obese population are, respectively, lower and higher than those found in normal population. In this study, an experimental-numerical approach was adopted to quantify the effect of this metabolic alteration found in obese population on the homeostasis of femoral hip cartilage. A new computational model, based on the mechano-electrochemical mixture theory, was developed to describe competitive binding kinetics of IGF-1 with IGFBP and CSR, and associated glycosaminoglycan (GAG) biosynthesis. Moreover, a gait analysis was carried out on obese and normal subjects to experimentally characterize mechanical loads on hip cartilage during walking. This information was deployed into the model to account for effects of physiologically relevant tissue deformation on GAG production in ECM. Numerical simulations were performed to compare GAG biosynthesis in femoral hip cartilage of normal and obese subjects. Results indicated that the lower ratio of IGF-1 to IGFBP found in obese population reduces cartilage GAG concentration up to 18 % when compared to normal population. Moreover, moderate physical activity, such as walking, has a modest beneficial effect on GAG production. The findings of this study suggest that IGF-1/IGFBP metabolic unbalance should be accounted for when considering the association of obesity with hip osteoarthritis.
Available from: Bhaskar Roy
- "– IGFs circulate in the bloodstream at nanomolar concentrations and are generally bound to one of six IGF binding proteins (IGFBPs), which regulate their availability to cell surface receptors.  Glycosaminoglycans also play a critical role in liberating the ligands from their binding proteins and making them available to bind receptors.  Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) share about 50% of amino acid sequence with insulin and have some affinity for the insulin receptor, but have distinct physiological functions from insulin mediated by signaling through the IGF-1 receptor. "
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ABSTRACT: The ability of embryonic stem cells to differentiate into endothelium and form functional blood vessels has been well established and can potentially be harnessed for therapeutic angiogenesis. However, after almost two decades of investigation in this field, limited knowledge exists for directing endothelial differentiation. A better understanding of the cellular mechanisms regulating vasculogenesis is required for the development of embryonic stem cell-based models and therapies. In this study, we elucidated the mechanistic role of insulin-like growth factors (IGF1 and 2) and IGF receptors (IGFR1 and 2) in endothelial differentiation using an embryonic stem cell embryoid body model. Both IGF1 or IGF2 predisposed embryonic stem to differentiate towards a mesodermal lineage, the endothelial precursor germ layer, as well as increased the generation of significantly more endothelial cells at later stages. Inhibition of IGFR1 signaling using neutralizing antibody or a pharmacological inhibitor, picropodophyllin, significantly reduced IGF-induced mesoderm and endothelial precursor cell formation. We confirmed that IGF-IGFR1 signaling stabilizes HIF1α and leads to up-regulation of VEGF during vasculogenesis in embryoid bodies. Understanding the mechanisms that are critical for vasculogenesis in various models will bring us one step closer to enabling cell based therapies for neovascularization.
Available from: Robert Michael Akers
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ABSTRACT: Interleukin-1 (IL-1) and insulin-like growth factor-I (IGF-I), which have opposing effects on matrix metabolism within articular cartilage, are thought to play prominent roles in the pathogenesis of osteoarthritis. To better understand the link between these anabolic (IGF-I) and catabolic (IL-1) stimuli, we examined exogenous IL-1 regulation of the IGF-I signaling system of articular chondrocytes (ACs). Equine ACs from non-arthritic stifle joints were expanded in monolayer culture, encapsulated for 10 days in alginate beads, and stimulated as high-density monolayers with recombinant equine IL-1beta (0, 1, 10 ng/ml) for 48 h. IL-1beta enhanced expression of IGF-IR levels, as determined by both [125I]-IGF-I binding studies and Western blotting, while reducing the concentration of endogenous IGF-I detected in conditioned media by radioimmunoassay. Western ligand blotting revealed that chondrocytes primarily secreted IGF binding proteins (IGFBPs) with molecular weights of 28-30 and 32-34 kDa, which were identified as IGFBPs 5 and 2, respectively, and that IL-1beta treatment diminished IGFBP-2, the prominent homolog in conditioned media. Northern blot analysis suggested IL-1beta regulation of IGF-I and, to some extent, IGF-IR was mediated by transcription; however, the cytokine did not affect IGFBP-2 expression. To test for evidence of proteolysis by matrix metalloproteinases (MMPs), additional cultures were co-incubated with inhibitors for MMPs 2/9, 3, and 8. IGFBP-2 suppression was partially reversed by gelatinase (MMP-2/9) inhibition. In summary, these findings further delineate the role of IL-1 as a key regulator of the IGF-I system within articular cartilage, demonstrating that regulation occurs through both direct (transcriptional) and indirect (proteolytic) mechanisms.
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