Journal article
Modeling the Insulin-Like growth factor system in articular cartilage
PloS one, Vol.8(6)
2013
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.
Details
- Title
- Modeling the Insulin-Like growth factor system in articular cartilage
- Authors/Creators
- L. Zhang (Author/Creator)D.W. Smith (Author/Creator)B.S. Gardiner (Author/Creator)A.J. Grodzinsky (Author/Creator)
- Publication Details
- PloS one, Vol.8(6)
- Publisher
- Public Library of Science
- Identifiers
- 991005543786607891
- Copyright
- © 2013 Zhang et al.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- 1 Clinical & Life Sciences
- 1.164 Endocrinology & Metabolism
- 1.164.287 GH/IGF Axis
- Web Of Science research areas
- Endocrinology & Metabolism
- ESI research areas
- Biology & Biochemistry