Proctor2013 - Cartilage breakdown, interventions to reduce collagen release

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:
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 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.

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