Show simple item record

dc.contributor.authorZhang, Lihai
dc.contributor.authorSmith, David W.
dc.contributor.authorGardiner, Bruce S.
dc.contributor.authorGrodzinsky, Alan J.
dc.date.accessioned2013-09-13T17:28:48Z
dc.date.available2013-09-13T17:28:48Z
dc.date.issued2013-06
dc.date.submitted2012-12
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/1721.1/80730
dc.description.abstractIGF 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.en_US
dc.description.sponsorshipNational Health and Medical Research Council (Australia) (APP1051455)en_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pone.0066870en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/en_US
dc.sourcePLoSen_US
dc.titleModeling the Insulin-Like Growth Factor System in Articular Cartilageen_US
dc.typeArticleen_US
dc.identifier.citationZhang, 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.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Center for Biomedical Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Electrical Engineering and Computer Scienceen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Mechanical Engineeringen_US
dc.contributor.mitauthorGrodzinsky, Alan J.en_US
dc.relation.journalPLoS ONEen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsZhang, Lihai; Smith, David W.; Gardiner, Bruce S.; Grodzinsky, Alan J.en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-4942-3456
mit.licensePUBLISHER_CCen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record