Proctor2013 - Cartilage breakdown, interventions to reduce collagen release

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Short description
Proctor2013 - Cartilage breakdown, interventions to reduce collagen release

The molecular pathways involved in cartilage breakdown is studied using this model to examine possible interventions to reduce cartilage collagen release. The model contains three separate submodels, one which describes the IL-1/JNK signalling pathway, secondly the OSM/STAT3 signalling pathway, and lastly a module which includes proMMP (Matrix matalloproteinase) activation, and aggrecan and collagen release.

This model is described in the article:

Proctor CJ, Macdonald C, Milner JM, Rowan AD, Cawston TE.
Arthritis Rheum. 2013 Nov 27.

Abstract:

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.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • 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.
Contributors
Carole Proctor

Metadata information

is
BioModels Database MODEL1305280001
BioModels Database BIOMD0000000504
isDescribedBy
PubMed 24285357
hasTaxon
Taxonomy Homo sapiens
isVersionOf
occursIn
Brenda Tissue Ontology chondrocyte
hasProperty
Human Disease Ontology cartilage disease
Mathematical Modelling Ontology Ordinary differential equation model
Curation status
Curated
Original model(s)
Proctor2013_Cartilage_CollagenRelease
Name Description Size Actions

Model file

BIOMD0000000504_url.xml SBML L2V4 representation of Proctor2013 - Cartilage breakdown, interventions to reduce collagen release 204.07 KB Preview | Download

Additional files

BIOMD0000000504.sci Auto-generated Scilab file 32.21 KB Preview | Download
BIOMD0000000504-biopax2.owl Auto-generated BioPAX (Level 2) 285.11 KB Preview | Download
BIOMD0000000504.svg Auto-generated Reaction graph (SVG) 457.09 KB Preview | Download
BIOMD0000000504.m Auto-generated Octave file 48.03 KB Preview | Download
BIOMD0000000504-biopax3.owl Auto-generated BioPAX (Level 3) 480.64 KB Preview | Download
BIOMD0000000504.vcml Auto-generated VCML file 897.00 bytes Preview | Download
BIOMD0000000504.xpp Auto-generated XPP file 36.02 KB Preview | Download
BIOMD0000000504_urn.xml Auto-generated SBML file with URNs 201.65 KB Preview | Download
BIOMD0000000504.png Auto-generated Reaction graph (PNG) 3.98 MB Preview | Download
BIOMD0000000504.pdf Auto-generated PDF file 827.24 KB Preview | Download

  • Model originally submitted by : Carole Proctor
  • Submitted: 28-May-2013 13:58:34
  • Last Modified: 16-Mar-2015 13:44:33
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 16-Mar-2015 13:44:33
    • 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: 28-May-2013 13:58:34
    • 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.