Modeling the Insulin-Like Growth Factor System in Articular Cartilage
Author(s)Zhang, Lihai; Smith, David W.; Gardiner, Bruce S.; Grodzinsky, Alan J.
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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.
DepartmentMassachusetts Institute of Technology. Center for Biomedical Engineering; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science; Massachusetts Institute of Technology. Department of Mechanical Engineering
Public Library of Science
Zhang, Lihai, David W. Smith, Bruce S. Gardiner, and Alan J. Grodzinsky. “Modeling the Insulin-Like Growth Factor System in Articular Cartilage.” Edited by Amina Ann Qutub. PLoS ONE 8, no. 6 (June 26, 2013): e66870.
Final published version