A computer simulation approach to assessing therapeutic intervention points for the prevention of cytokine-induced cartilage breakdown.
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.


CONCLUSIONS
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.
MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing and Newcastle University, Newcastle upon Tyne, UK.
C J
CJ
Proctor
C
C
Macdonald
J M
JM
Milner
A D
AD
Rowan
T E
TE
Cawston
D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003198:Computer Simulation; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D053683:Oncostatin M / Q000494:pharmacology / Q000627:therapeutic use; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
D007375:Interleukin-1; D053683:Oncostatin M