title: Modeling the Insulin-Like Growth Factor System in Articular Cartilage.
abstract: IGF signaling is involved in cell proliferation, differentiation and apoptosis in a wide range of tissues, both normal and diseased, and so IGF-IR has been the focus of intense interest as a promising drug target. In this computational study on cartilage, we focus on two questions: (i) what are the key factors influencing IGF-IR complex formation, and (ii) how might cells regulate IGF-IR complex formation? We develop a reaction-diffusion computational model of the IGF system involving twenty three parameters. A series of parametric and sensitivity studies are used to identify the key factors influencing IGF signaling. From the model we predict the free IGF and IGF-IR complex concentrations throughout the tissue. We estimate the degradation half-lives of free IGF-I and IGFBPs in normal cartilage to be 20 and 100 mins respectively, and conclude that regulation of the IGF half-life, either directly or indirectly via extracellular matrix IGF-BP protease concentrations, are two critical factors governing the IGF-IR complex formation in the cartilage. Further we find that cellular regulation of IGF-II production, the IGF-IIR concentration and its clearance rate, all significantly influence IGF signaling. It is likely that negative feedback processes via regulation of these factors tune IGF signaling within a tissue, which may help explain the recent failures of single target drug therapies aimed at modifying IGF signaling.
authors.affiliation: Department of Infrastructure Engineering, The University of Melbourne, Victoria, Australia.
authors.forename: Lihai
authors.initials: L
authors.lastname: Zhang
authors.forename: David W
authors.initials: DW
authors.lastname: Smith
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Gardiner
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Grodzinsky
mesh_terms: D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II