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A Computer Simulation Approach to Assessing Therapeutic Intervention Points for the Prevention of Cytokine‐Induced Cartilage Breakdown
Author(s) -
Proctor C. J.,
Macdonald C.,
Milner J. M.,
Rowan A. D.,
Cawston T. E.
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38297
Subject(s) - oncostatin m , collagenase , cartilage , microbiology and biotechnology , matrix metalloproteinase , cytokine , signal transduction , p38 mitogen activated protein kinases , interleukin 6 , chemistry , computer science , mapk/erk pathway , biology , immunology , biochemistry , enzyme , anatomy
Objective To use a novel computational approach to examine the molecular pathways involved in cartilage breakdown and to use computer simulation to test possible interventions for reducing collagen release. Methods We constructed a computational model of the relevant molecular pathways using the Systems Biology Markup Language, a computer‐readable format of a biochemical network. The model was constructed using our experimental data showing that interleukin‐1 (IL‐1) and oncostatin M (OSM) act synergistically to up‐regulate collagenase protein levels and activity and initiate cartilage collagen breakdown. Simulations were performed using the COPASI software package. Results The model predicted that simulated inhibition of JNK or p38 MAPK, and overexpression of tissue inhibitor of metalloproteinases 3 (TIMP‐3) led to a reduction in collagen release. Overexpression of TIMP‐1 was much less effective than that of TIMP‐3 and led to a delay, rather than a reduction, in collagen release. Simulated interventions of receptor antagonists and inhibition of JAK‐1, the first kinase in the OSM pathway, were ineffective. So, importantly, the model predicts that it is more effective to intervene at targets that are downstream, such as the JNK pathway, rather than those that are close to the cytokine signal. In vitro experiments confirmed the effectiveness of JNK inhibition. Conclusion Our study shows the value of computer modeling as a tool for examining possible interventions by which to reduce cartilage collagen breakdown. The model predicts that interventions that either prevent transcription or inhibit the activity of collagenases are promising strategies and should be investigated further in an experimental setting.