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Proctor2013 - Cartilage breakdown, interventions to reduce collagen release

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  • A computer simulation approach for assessing therapeutic intervention points to prevent cytokine-induced cartilage breakdown.
  • Proctor CJ, Macdonald C, Milner JM, Rowan AD, Cawston TE.
  • Arthritis Rheum. 2013 Nov; : 2013
  • MRC-Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing; Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
  • 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 to reduce collagen release. Methods. We constructed a computational model of the relevant molecular pathways using the Systems Biology Markup Language (SBML), 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 and activity and initiate cartilage collagen breakdown. Simulations were performed in the COPASI software package. Results. The model predicted that simulated inhibition of c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase, and over-expression of tissue inhibitor of metalloproteinases 3 (TIMP-3) led to a reduction in collagen release. Over-expression of TIMP-1 was much less effective than TIMP-3 and led to a delay, rather than a reduction, in collagen release. Simulated interventions of receptor antagonists and inhibition of Janus kinase 1 (JAK1), the first kinase in the OSM pathway, were ineffective. So, importantly, the model predicts that it is more effective to intervene at targets which are downstream, such as the JNK pathway, rather than close to the cytokine signal. In vitro experiments confirmed the effectiveness of JNK inhibition. Conclusion. Our study shows the value of computer modelling as a tool for examining possible interventions to reduce cartilage collagen breakdown. The model predicts interventions that either prevent transcription or inhibit activity of collagenases are promising strategies and should be investigated further in an experimental setting. © 2013 American College of Rheumatology.
Carole Proctor

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  • Model originally submitted by : Carole Proctor
  • Submitted: May 28, 2013 1:58:34 PM
  • Last Modified: Mar 16, 2015 1:44:33 PM
  • Version: 2 public model Download this version
    • Submitted on: Mar 16, 2015 1:44:33 PM
    • Submitted by: Carole Proctor
    • With comment: Current version of Proctor2013 - Cartilage breakdown, interventions to reduce collagen release
  • Version: 1 public model Download this version
    • Submitted on: May 28, 2013 1:58:34 PM
    • Submitted by: Carole Proctor
    • With comment: Original import of BIOMD0000000504.xml.origin
Curator's comment:
(added: 10 Jan 2014, 16:53:54, updated: 10 Jan 2014, 16:53:54)
Figure 1 of the reference publication is reproduced here. The model as such reproduces figure C (in the presence of both IL1 (=100) and OSM (=1000)). To reproduce figures A (IL-1 only), set IL1 = 100 and OSM = 0. To reproduce figure B (OSM only), set IL1 = 0 and OSM - 1000. The simulation was done using SBML odeSolver. The plots were generated using Gnuplot.