BioModels Database logo

BioModels Database

spacer

BIOMD0000000504 - Proctor2013 - Cartilage breakdown, interventions to reduce collagen release

 

 |   |   |  Send feedback
Reference Publication
Publication ID: 24285357
Proctor CJ, Macdonald C, Milner JM, Rowan AD, Cawston TE.
A computer simulation approach for assessing therapeutic intervention points to prevent cytokine-induced cartilage breakdown.
Arthritis Rheum. 2013 Nov; :
MRC-Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing; Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.  [more]
Model
Original Model: Proctor2013_Cartilage_Coll...
Submitter: Carole Proctor
Submission ID: MODEL1305280001
Submission Date: 28 May 2013 13:58:34 UTC
Last Modification Date: 16 Mar 2015 13:44:33 UTC
Creation Date: 10 Jan 2014 16:54:21 UTC
Encoders:  Vijayalakshmi Chelliah
   Carole Proctor
set #1
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #2
bqbiol:hasProperty Human Disease Ontology cartilage disease
set #3
bqbiol:isVersionOf Gene Ontology regulation of collagen catabolic process
set #4
bqbiol:hasTaxon Taxonomy Homo sapiens
set #5
bqbiol:occursIn Brenda Tissue Ontology chondrocyte
Notes
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.

Model
Publication ID: 24285357 Submission Date: 28 May 2013 13:58:34 UTC Last Modification Date: 16 Mar 2015 13:44:33 UTC Creation Date: 10 Jan 2014 16:54:21 UTC
Mathematical expressions
Reactions
IL1binding IL1release IL1antagonistbinding IL1antagonistrelease
IL1degradation IRAK2binding IRAK2release TRAF6binding
TRAF6release JNKphosphorylation JNKdephosphorylation JNKdephosphorylationByDUSP16
cJunPhosphorylation cJunDephosphorylation cJunDimerisation cJunDedimerisation
cJunTranscriptionAP1 cJunTranscriptioncJun cJunBasalTranscription cJunmRNADegradation
cJunTranslation cJunDegradation p38phosphorylation p38dephosphorylation
p38dephosphorylationMKP1 MMP1Transcription_AP1 MMP1Transcription_cJun_dimer MMP1Translation
MMP1mRNADegradation proMMP1cleavageByMatriptase proMMP1cleavageByMMP3 MMP1Degradation
MMP3Transcription_AP1 MMP3Transcription_cJun_dimer MMP3Translation MMP3mRNADegradation
proMMP3cleavageByMatriptase MMP3Degradation MMP13Transcription_AP1 MMP13Transcription_cJun_dimer
MMP13Translation MMP13mRNADegradation proMMP13cleavageByMMP3 MMP13Degradation
TIMP1Translation TIMP1mRNADegradation TIMP1Degradation ADAMTS4Transcription_AP1
ADAMTS4Transcription_cJun_dimer ADAMTS4Translation ADAMTS4mRNADegradation ADAMTS4Degradation
PP4Synthesis PP4Synthesis_cJun_dimer DUSP16Synthesis DUSP16Synthesis_cJun_dimer
PP4Degradation DUSP16Degradation TRAF6Inhibition BoundTRAF6Inhibition
TRAF6PP4Disassociation IRAK2_TRAF6PP4Disassociation Transcription_cFos_byAP1 cFosmRNA_Degradation
cFosSynthesis cFosDegradation cFosPhosphorylation_p38 cFosDephosphorylation
MKP1Synthesis MKP1Synthesis_cJun_dimer MKP1Degradation cFosDephosphorylationByDusp16
cFoscJunBinding cFoscJunRelease OSM_OSMR_binding OSM_OSMR_release
OSM_OSMRa_binding OSM_OSMRa_release JAK1_Phosphorylation JAK1_Dephosphorylation
JAK1_DephosphorylationByPTPRT STAT3_Phosphorylation STAT3_cyt_Dephosphorylation STAT3_cyt_DephosphorylationByPTPRT
STAT3_nuc_Dephosphorylation STAT3_nuc_DephosphorylationByPTPRT STAT3_transport_to_nucleus STAT3_transport_from_nucleus
cFos_induction_by_STAT3 PTPRT_induction_by_STAT3 PTPRT_degradation STAT3_induction_of_SOCS3
SOCS3mRNAdegradation SOCS3_translation SOCS3_degradation SOCS3_OSMR_binding
SOCS3_OSMR_release OSM_degradation MMP1InhibtionByTIMP1 MMP1_TIMP1release
MMP3InhibtionByTIMP1 MMP3_TIMP1release MMP13InhibtionByTIMP1 MMP13_TIMP1release
ADAMTS4InhibtionByTIMP1 ADAMTS4_TIMP1release Collagen2DegradationByMMP1 Collagen2DegradationByMMP13
AggrecanDegradationByADAMTS4 MatriptaseSynthesis MatriptaseDegradation SP1Synthesis
SP1Degradation SP1_TIMP1_DNAbinding SP1_TIMP1_DNArelease TIMP1_transcription_STAT3
TIMP1BasalTranscription TIMP1Transcription_AP1 TIMP3BasalTranscriptionn TIMP3Transcription_AP1
TIMP3Transcription_STAT3 TIMP3Translation TIMP3mRNADegradation TIMP3Degradation
ADAMTS4InhibitionByTimp3 ADAMTS4_TIMP3release MMP1InhibtionByTIMP3 MMP1_TIMP3release
MMP3InhibtionByTIMP3 MMP3_TIMP3release MMP13InhibtionByTIMP3 MMP13_TIMP3release
Physical entities
Compartments Species
cytoplasm ADAMTS4_mRNA cFos cFos_mRNA
cJun cJun_mRNA DUSP16
IRAK2 IRAK2_TRAF6 IRAK2_TRAF6_PP4
JAK1 JAK1_P JNK
JNK_P Matriptase MKP1
MMP1_mRNA MMP3_mRNA MMP13_mRNA
p38 p38_P PP4
proMMP1 proMMP3 proMMP13
PTPRT SOCS3 SOCS3_mRNA
STAT3_cyt STAT3_P_cyt TIMP1_mRNA
TIMP3_mRNA TRAF6 TRAF6_PP4
Source Sink  
nucleus cFos_cJun cFos_P cJun_P
cJun_dimer SP1 SP1_TIMP1_DNA
STAT3_nuc STAT3_P_nuc TIMP1_DNA
     
membrane IL1_IL1R IL1_IL1Ra IL1_IL1R_IRAK2
IL1R IL1Ra OSM_OSMR
OSM_OSMRa OSMR_SOCS3 OSMR
OSMRa    
ecm ADAMTS4 ADAMTS4_TIMP1 ADAMTS4_TIMP3
Aggrecan Aggrecan_Collagen2 AggFrag
ColFrag Collagen2 IL1
MMP1 MMP1_TIMP1 MMP1_TIMP3
MMP3 MMP3_TIMP1 MMP3_TIMP3
MMP13 MMP13_TIMP1 MMP13_TIMP3
OSM TIMP1 TIMP3
     
Global parameters
kactMMP13mmp3 kactMMP1mat kactMMP1mmp3 kactMMP3mat
kAP1activity kbincFoscJun kbinIL1IL1R kbinIL1IL1Ra
kbinIRAK2 kbinOSMOSMR kbinOSMOSMRa kbinSOCS3OSMR
kbinSP1TIMP1DNA kbinTRAF6 kcyt2nucSTAT3 kdedimercJun
kdegADAMTS4 kdegADAMTS4mRNA kdegAggrecan kdegcFos
kdegcFosmRNA kdegcJun kdegcJunmRNA kdegCollagen2mmp1
kdegCollagen2mmp13 kdegDUSP16 kdegIL1 kdegMatriptase
kdegMKP1 kdegMMP1 kdegMMP13 kdegMMP13mRNA
kdegMMP1mRNA kdegMMP3 kdegMMP3mRNA kdegOSM
kdegPP4 kdegPTPRT kdegSOCS3 kdegSOCS3mRNA
kdegSP1 kdegTIMP1 kdegTIMP1mRNA kdegTIMP3
kdegTIMP3mRNA kdephoscFos kdephoscFosDUSP16 kdephoscJun
kdephosJAK1 kdephosJAK1PTPRT kdephosJNK kdephosJNKDUSP16
kdephosp38 kdephosp38MKP1 kdephosSTAT3 kdephosSTAT3nuc
kdephosSTAT3nucPTPRT kdephosSTAT3PTPRT kdimercJun kinhibADAMTS4TIMP1
kinhibADAMTS4TIMP3 kinhibMMP13TIMP1 kinhibMMP13TIMP3 kinhibMMP1TIMP1
kinhibMMP1TIMP3 kinhibMMP3TIMP1 kinhibMMP3TIMP3 kinhibTRAF6
knuc2cytSTAT3 kphoscFos kphoscJun kphosJAK1
kphosJNK kphosp38 kphosSTAT3 krelADAMTS4TIMP1
krelADAMTS4TIMP3 krelcFoscJun krelIL1IL1R krelIL1IL1Ra
krelIRAK2 krelMMP1 krelMMP13 krelMMP13TIMP3
krelMMP1TIMP3 krelMMP3 krelMMP3TIMP3 krelOSMOSMR
krelOSMOSMRa krelSOCS3OSMR krelSP1TIMP1DNA krelTRAF6
krelTRAF6PP4 ksynADAMTS4 ksynADAMTS4mRNA ksynADAMTS4mRNAcJun
ksynbasalcJunmRNA ksynbasalTIMP1mRNA ksynbasalTIMP3mRNA ksyncFos
ksyncFosmRNA ksyncFosmRNAStat3 ksyncJun ksyncJunmRNA
ksyncJunmRNAcJun ksynDUSP16 ksynDUSP16cJun ksynMatriptase
ksynMKP1 ksynMKP1cJun ksynMMP1 ksynMMP13
ksynMMP13mRNA ksynMMP13mRNAcJun ksynMMP1mRNA ksynMMP1mRNAcJun
ksynMMP3 ksynMMP3mRNA ksynMMP3mRNAcJun ksynPP4
ksynPP4cJun ksynPTPRT ksynSOCS3 ksynSOCS3mRNA
ksynSP1 ksynTIMP1 ksynTIMP1mRNA ksynTIMP1mRNAStat3
ksynTIMP3 ksynTIMP3mRNA ksynTIMP3mRNAStat3  
Reactions (132)
 
 IL1binding [IL1] + [IL1R] → [IL1_IL1R];   {IL1} , {IL1R}
 
 IL1release [IL1_IL1R] → [IL1] + [IL1R];   {IL1_IL1R}
 
 IL1antagonistbinding [IL1] + [IL1Ra] → [IL1_IL1Ra];   {IL1} , {IL1Ra}
 
 IL1antagonistrelease [IL1_IL1Ra] → [IL1] + [IL1Ra];   {IL1_IL1Ra}
 
 IL1degradation [IL1] → [Sink];   {IL1}
 
 IRAK2binding [IL1_IL1R] + [IRAK2] → [IL1_IL1R_IRAK2];   {IL1_IL1R} , {IRAK2}
 
 IRAK2release [IL1_IL1R_IRAK2] → [IL1_IL1R] + [IRAK2];   {IL1_IL1R_IRAK2}
 
 TRAF6binding [IL1_IL1R_IRAK2] + [TRAF6] → [IL1_IL1R] + [IRAK2_TRAF6];   {IL1_IL1R_IRAK2} , {TRAF6}
 
 TRAF6release [IRAK2_TRAF6] → [IRAK2] + [TRAF6];   {IRAK2_TRAF6}
 
 JNKphosphorylation [JNK] + [IRAK2_TRAF6] → [JNK_P] + [IRAK2_TRAF6];   {JNK} , {IRAK2_TRAF6}
 
 JNKdephosphorylation [JNK_P] → [JNK];   {JNK_P}
 
 JNKdephosphorylationByDUSP16 [JNK_P] + [DUSP16] → [JNK] + [DUSP16];   {JNK_P} , {DUSP16}
 
 cJunPhosphorylation [cJun] + [JNK_P] → [cJun_P] + [JNK_P];   {cJun} , {JNK_P}
 
 cJunDephosphorylation [cJun_P] → [cJun];   {cJun_P}
 
 cJunDimerisation 2.0 × [cJun_P] → [cJun_dimer];   {cJun_P}
 
 cJunDedimerisation [cJun_dimer] → 2.0 × [cJun_P];   {cJun_dimer}
 
 cJunTranscriptionAP1 [cFos_cJun] → [cJun_mRNA] + [cFos_cJun];   {cFos_cJun}
 
 cJunTranscriptioncJun [cJun_dimer] → [cJun_mRNA] + [cJun_dimer];   {cJun_dimer}
 
 cJunBasalTranscription [Source] → [cJun_mRNA];   {Source}
 
 cJunmRNADegradation [cJun_mRNA] → [Sink];   {cJun_mRNA}
 
 cJunTranslation [cJun_mRNA] → [cJun_mRNA] + [cJun];   {cJun_mRNA}
 
 cJunDegradation [cJun] → [Sink];   {cJun}
 
 p38phosphorylation [p38] + [IRAK2_TRAF6] → [p38_P] + [IRAK2_TRAF6];   {p38} , {IRAK2_TRAF6}
 
 p38dephosphorylation [p38_P] → [p38];   {p38_P}
 
 p38dephosphorylationMKP1 [p38_P] + [MKP1] → [p38] + [MKP1];   {p38_P} , {MKP1}
 
 MMP1Transcription_AP1 [cFos_cJun] → [cFos_cJun] + [MMP1_mRNA];   {cFos_cJun}
 
 MMP1Transcription_cJun_dimer [cJun_dimer] → [cJun_dimer] + [MMP1_mRNA];   {cJun_dimer}
 
 MMP1Translation [MMP1_mRNA] → [MMP1_mRNA] + [proMMP1];   {MMP1_mRNA}
 
 MMP1mRNADegradation [MMP1_mRNA] → [Sink];   {MMP1_mRNA}
 
 proMMP1cleavageByMatriptase [proMMP1] + [Matriptase] → [MMP1] + [Matriptase];   {proMMP1} , {Matriptase}
 
 proMMP1cleavageByMMP3 [proMMP1] + [MMP3] → [MMP1] + [MMP3];   {proMMP1} , {MMP3}
 
 MMP1Degradation [MMP1] → [Sink];   {MMP1}
 
 MMP3Transcription_AP1 [cFos_cJun] → [cFos_cJun] + [MMP3_mRNA];   {cFos_cJun}
 
 MMP3Transcription_cJun_dimer [cJun_dimer] → [cJun_dimer] + [MMP3_mRNA];   {cJun_dimer}
 
 MMP3Translation [MMP3_mRNA] → [MMP3_mRNA] + [proMMP3];   {MMP3_mRNA}
 
 MMP3mRNADegradation [MMP3_mRNA] → [Sink];   {MMP3_mRNA}
 
 proMMP3cleavageByMatriptase [proMMP3] + [Matriptase] → [MMP3] + [Matriptase];   {proMMP3} , {Matriptase}
 
 MMP3Degradation [MMP3] → [Sink];   {MMP3}
 
 MMP13Transcription_AP1 [cFos_cJun] → [cFos_cJun] + [MMP13_mRNA];   {cFos_cJun}
 
 MMP13Transcription_cJun_dimer [cJun_dimer] → [cJun_dimer] + [MMP13_mRNA];   {cJun_dimer}
 
 MMP13Translation [MMP13_mRNA] → [MMP13_mRNA] + [proMMP13];   {MMP13_mRNA}
 
 MMP13mRNADegradation [MMP13_mRNA] → [Sink];   {MMP13_mRNA}
 
 proMMP13cleavageByMMP3 [proMMP13] + [MMP3] → [MMP13] + [MMP3];   {proMMP13} , {MMP3}
 
 MMP13Degradation [MMP13] → [Sink];   {MMP13}
 
 TIMP1Translation [TIMP1_mRNA] → [TIMP1_mRNA] + [TIMP1];   {TIMP1_mRNA}
 
 TIMP1mRNADegradation [TIMP1_mRNA] → [Sink];   {TIMP1_mRNA}
 
 TIMP1Degradation [TIMP1] → [Sink];   {TIMP1}
 
 ADAMTS4Transcription_AP1 [cFos_cJun] → [cFos_cJun] + [ADAMTS4_mRNA];   {cFos_cJun}
 
 ADAMTS4Transcription_cJun_dimer [cJun_dimer] → [cJun_dimer] + [ADAMTS4_mRNA];   {cJun_dimer}
 
 ADAMTS4Translation [ADAMTS4_mRNA] → [ADAMTS4_mRNA] + [ADAMTS4];   {ADAMTS4_mRNA}
 
 ADAMTS4mRNADegradation [ADAMTS4_mRNA] → [Sink];   {ADAMTS4_mRNA}
 
 ADAMTS4Degradation [ADAMTS4] → [Sink];   {ADAMTS4}
 
 PP4Synthesis [cFos_cJun] → [cFos_cJun] + [PP4];   {cFos_cJun}
 
 PP4Synthesis_cJun_dimer [cJun_dimer] → [cJun_dimer] + [PP4];   {cJun_dimer}
 
 DUSP16Synthesis [cFos_cJun] → [cFos_cJun] + [DUSP16];   {cFos_cJun}
 
 DUSP16Synthesis_cJun_dimer [cJun_dimer] → [cJun_dimer] + [DUSP16];   {cJun_dimer}
 
 PP4Degradation [PP4] → [Sink];   {PP4}
 
 DUSP16Degradation [DUSP16] → [Sink];   {DUSP16}
 
 TRAF6Inhibition [TRAF6] + [PP4] → [TRAF6_PP4];   {TRAF6} , {PP4}
 
 BoundTRAF6Inhibition [IRAK2_TRAF6] + [PP4] → [IRAK2_TRAF6_PP4];   {IRAK2_TRAF6} , {PP4}
 
 TRAF6PP4Disassociation [TRAF6_PP4] → [TRAF6] + [PP4];   {TRAF6_PP4}
 
 IRAK2_TRAF6PP4Disassociation [IRAK2_TRAF6_PP4] → [IRAK2_TRAF6] + [PP4];   {IRAK2_TRAF6_PP4}
 
 Transcription_cFos_byAP1 [cFos_cJun] → [cFos_cJun] + [cFos_mRNA];   {cFos_cJun}
 
 cFosmRNA_Degradation [cFos_mRNA] → [Sink];   {cFos_mRNA}
 
 cFosSynthesis [cFos_mRNA] → [cFos_mRNA] + [cFos];   {cFos_mRNA}
 
 cFosDegradation [cFos] → [Sink];   {cFos}
 
 cFosPhosphorylation_p38 [p38_P] + [cFos] → [p38_P] + [cFos_P];   {p38_P} , {cFos}
 
 cFosDephosphorylation [cFos_P] → [cFos];   {cFos_P}
 
 MKP1Synthesis [cFos_cJun] → [MKP1] + [cFos_cJun];   {cFos_cJun}
 
 MKP1Synthesis_cJun_dimer [cJun_dimer] → [MKP1] + [cJun_dimer];   {cJun_dimer}
 
 MKP1Degradation [MKP1] → [Sink];   {MKP1}
 
 cFosDephosphorylationByDusp16 [cFos_P] + [DUSP16] → [cFos] + [DUSP16];   {cFos_P} , {DUSP16}
 
 cFoscJunBinding [cFos_P] + [cJun_P] → [cFos_cJun];   {cFos_P} , {cJun_P}
 
 cFoscJunRelease [cFos_cJun] → [cFos_P] + [cJun_P];   {cFos_cJun}
 
 OSM_OSMR_binding [OSM] + [OSMR] → [OSM_OSMR];   {OSM} , {OSMR}
 
 OSM_OSMR_release [OSM_OSMR] → [OSM] + [OSMR];   {OSM_OSMR}
 
 OSM_OSMRa_binding [OSM] + [OSMRa] → [OSM_OSMRa];   {OSM} , {OSMRa}
 
 OSM_OSMRa_release [OSM_OSMRa] → [OSM] + [OSMRa];   {OSM_OSMRa}
 
 JAK1_Phosphorylation [JAK1] + [OSM_OSMR] → [JAK1_P] + [OSM_OSMR];   {JAK1} , {OSM_OSMR}
 
 JAK1_Dephosphorylation [JAK1_P] → [JAK1];   {JAK1_P}
 
 JAK1_DephosphorylationByPTPRT [JAK1_P] + [PTPRT] → [JAK1] + [PTPRT];   {JAK1_P} , {PTPRT}
 
 STAT3_Phosphorylation [STAT3_cyt] + [JAK1_P] → [STAT3_P_cyt] + [JAK1_P];   {STAT3_cyt} , {JAK1_P}
 
 STAT3_cyt_Dephosphorylation [STAT3_P_cyt] → [STAT3_cyt];   {STAT3_P_cyt}
 
 STAT3_cyt_DephosphorylationByPTPRT [STAT3_P_cyt] + [PTPRT] → [STAT3_cyt] + [PTPRT];   {STAT3_P_cyt} , {PTPRT}
 
 STAT3_nuc_Dephosphorylation [STAT3_P_nuc] → [STAT3_nuc];   {STAT3_P_nuc}
 
 STAT3_nuc_DephosphorylationByPTPRT [STAT3_P_nuc] + [PTPRT] → [STAT3_nuc] + [PTPRT];   {STAT3_P_nuc} , {PTPRT}
 
 STAT3_transport_to_nucleus [STAT3_P_cyt] → [STAT3_P_nuc];   {STAT3_P_cyt}
 
 STAT3_transport_from_nucleus [STAT3_nuc] → [STAT3_cyt];   {STAT3_nuc}
 
 cFos_induction_by_STAT3 [STAT3_P_nuc] → [STAT3_P_nuc] + [cFos_mRNA];   {STAT3_P_nuc}
 
 PTPRT_induction_by_STAT3 [STAT3_P_nuc] → [STAT3_P_nuc] + [PTPRT];   {STAT3_P_nuc}
 
 PTPRT_degradation [PTPRT] → [Sink];   {PTPRT}
 
 STAT3_induction_of_SOCS3 [STAT3_P_nuc] → [STAT3_P_nuc] + [SOCS3_mRNA];   {STAT3_P_nuc}
 
 SOCS3mRNAdegradation [SOCS3_mRNA] → [Sink];   {SOCS3_mRNA}
 
 SOCS3_translation [SOCS3_mRNA] → [SOCS3_mRNA] + [SOCS3];   {SOCS3_mRNA}
 
 SOCS3_degradation [SOCS3] → [Sink];   {SOCS3}
 
 SOCS3_OSMR_binding [SOCS3] + [OSMR] → [OSMR_SOCS3];   {SOCS3} , {OSMR}
 
 SOCS3_OSMR_release [OSMR_SOCS3] → [SOCS3] + [OSMR];   {OSMR_SOCS3}
 
 OSM_degradation [OSM] → [Sink];   {OSM}
 
 MMP1InhibtionByTIMP1 [MMP1] + [TIMP1] → [MMP1_TIMP1];   {MMP1} , {TIMP1}
 
 MMP1_TIMP1release [MMP1_TIMP1] → [MMP1] + [TIMP1];   {MMP1_TIMP1}
 
 MMP3InhibtionByTIMP1 [MMP3] + [TIMP1] → [MMP3_TIMP1];   {MMP3} , {TIMP1}
 
 MMP3_TIMP1release [MMP3_TIMP1] → [MMP3] + [TIMP1];   {MMP3_TIMP1}
 
 MMP13InhibtionByTIMP1 [MMP13] + [TIMP1] → [MMP13_TIMP1];   {MMP13} , {TIMP1}
 
 MMP13_TIMP1release [MMP13_TIMP1] → [MMP13] + [TIMP1];   {MMP13_TIMP1}
 
 ADAMTS4InhibtionByTIMP1 [ADAMTS4] + [TIMP1] → [ADAMTS4_TIMP1];   {ADAMTS4} , {TIMP1}
 
 ADAMTS4_TIMP1release [ADAMTS4_TIMP1] → [ADAMTS4] + [TIMP1];   {ADAMTS4_TIMP1}
 
 Collagen2DegradationByMMP1 [Collagen2] + [MMP1] → [MMP1] + [ColFrag];   {Collagen2} , {MMP1}
 
 Collagen2DegradationByMMP13 [Collagen2] + [MMP13] → [MMP13] + [ColFrag];   {Collagen2} , {MMP13}
 
 AggrecanDegradationByADAMTS4 [Aggrecan_Collagen2] + [ADAMTS4] → [ADAMTS4] + [Collagen2] + [AggFrag];   {Aggrecan_Collagen2} , {ADAMTS4}
 
 MatriptaseSynthesis [cFos_cJun] → [Matriptase] + [cFos_cJun];   {cFos_cJun}
 
 MatriptaseDegradation [Matriptase] → [Sink];   {Matriptase}
 
 SP1Synthesis [cFos_cJun] → [SP1] + [cFos_cJun];   {cFos_cJun}
 
 SP1Degradation [SP1] → [Sink];   {SP1}
 
 SP1_TIMP1_DNAbinding [SP1] + [TIMP1_DNA] → [SP1_TIMP1_DNA];   {SP1} , {TIMP1_DNA}
 
 SP1_TIMP1_DNArelease [SP1_TIMP1_DNA] → [SP1] + [TIMP1_DNA];   {SP1_TIMP1_DNA}
 
 TIMP1_transcription_STAT3 [STAT3_P_nuc] + [TIMP1_DNA] → [STAT3_P_nuc] + [TIMP1_DNA] + [TIMP1_mRNA];   {STAT3_P_nuc} , {TIMP1_DNA}
 
 TIMP1BasalTranscription [TIMP1_DNA] → [TIMP1_mRNA] + [TIMP1_DNA];   {TIMP1_DNA}
 
 TIMP1Transcription_AP1 [cFos_cJun] + [TIMP1_DNA] → [cFos_cJun] + [TIMP1_mRNA] + [TIMP1_DNA];   {cFos_cJun} , {TIMP1_DNA}
 
 TIMP3BasalTranscriptionn [Source] → [TIMP3_mRNA];   {Source}
 
 TIMP3Transcription_AP1 [cFos_cJun] → [cFos_cJun] + [TIMP3_mRNA];   {cFos_cJun}
 
 TIMP3Transcription_STAT3 [STAT3_P_nuc] → [STAT3_P_nuc] + [TIMP3_mRNA];   {STAT3_P_nuc}
 
 TIMP3Translation [TIMP3_mRNA] → [TIMP3_mRNA] + [TIMP3];   {TIMP3_mRNA}
 
 TIMP3mRNADegradation [TIMP3_mRNA] → [Sink];   {TIMP3_mRNA}
 
 TIMP3Degradation [TIMP3] → [Sink];   {TIMP3}
 
 ADAMTS4InhibitionByTimp3 [TIMP3] + [ADAMTS4] → [ADAMTS4_TIMP3];   {TIMP3} , {ADAMTS4}
 
 ADAMTS4_TIMP3release [ADAMTS4_TIMP3] → [ADAMTS4] + [TIMP3];   {ADAMTS4_TIMP3}
 
 MMP1InhibtionByTIMP3 [MMP1] + [TIMP3] → [MMP1_TIMP3];   {MMP1} , {TIMP3}
 
 MMP1_TIMP3release [MMP1_TIMP3] → [MMP1] + [TIMP3];   {MMP1_TIMP3}
 
 MMP3InhibtionByTIMP3 [MMP3] + [TIMP3] → [MMP3_TIMP3];   {MMP3} , {TIMP3}
 
 MMP3_TIMP3release [MMP3_TIMP3] → [MMP3] + [TIMP3];   {MMP3_TIMP3}
 
 MMP13InhibtionByTIMP3 [MMP13] + [TIMP3] → [MMP13_TIMP3];   {MMP13} , {TIMP3}
 
 MMP13_TIMP3release [MMP13_TIMP3] → [MMP13] + [TIMP3];   {MMP13_TIMP3}
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 ADAMTS4_mRNA
Compartment: cytoplasm
Initial amount: 0.0
 
 cFos
Compartment: cytoplasm
Initial amount: 0.0
 
 cFos_mRNA
Compartment: cytoplasm
Initial amount: 0.0
 
 cJun
Compartment: cytoplasm
Initial amount: 100.0
 
 cJun_mRNA
Compartment: cytoplasm
Initial amount: 5.0
 
 DUSP16
Compartment: cytoplasm
Initial amount: 0.0
 
 IRAK2
Compartment: cytoplasm
Initial amount: 100.0
 
 IRAK2_TRAF6
Compartment: cytoplasm
Initial amount: 0.0
 
 IRAK2_TRAF6_PP4
Compartment: cytoplasm
Initial amount: 0.0
 
 JAK1
Compartment: cytoplasm
Initial amount: 100.0
 
 JAK1_P
Compartment: cytoplasm
Initial amount: 0.0
 
 JNK
Compartment: cytoplasm
Initial amount: 100.0
 
 JNK_P
Compartment: cytoplasm
Initial amount: 0.0
 
 Matriptase
Compartment: cytoplasm
Initial amount: 100.0
 
 MKP1
Compartment: cytoplasm
Initial amount: 0.0
 
 MMP1_mRNA
Compartment: cytoplasm
Initial amount: 0.0
 
 MMP3_mRNA
Compartment: cytoplasm
Initial amount: 0.0
 
 MMP13_mRNA
Compartment: cytoplasm
Initial amount: 0.0
 
 p38
Compartment: cytoplasm
Initial amount: 100.0
 
 p38_P
Compartment: cytoplasm
Initial amount: 0.0
 
 PP4
Compartment: cytoplasm
Initial amount: 0.0
 
 proMMP1
Compartment: cytoplasm
Initial amount: 0.0
 
 proMMP3
Compartment: cytoplasm
Initial amount: 0.0
 
 proMMP13
Compartment: cytoplasm
Initial amount: 0.0
 
 PTPRT
Compartment: cytoplasm
Initial amount: 0.0
 
 SOCS3
Compartment: cytoplasm
Initial amount: 0.0
 
 SOCS3_mRNA
Compartment: cytoplasm
Initial amount: 0.0
 
 STAT3_cyt
Compartment: cytoplasm
Initial amount: 100.0
 
 STAT3_P_cyt
Compartment: cytoplasm
Initial amount: 0.0
 
 TIMP1_mRNA
Compartment: cytoplasm
Initial amount: 20.0
 
 TIMP3_mRNA
Compartment: cytoplasm
Initial amount: 20.0
 
 TRAF6
Compartment: cytoplasm
Initial amount: 100.0
 
 TRAF6_PP4
Compartment: cytoplasm
Initial amount: 0.0
 
 Source
Compartment: cytoplasm
Initial amount: 1.0
Constant
 
 Sink
Compartment: cytoplasm
Initial amount: 1.0
Constant
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 cFos_cJun
Compartment: nucleus
Initial amount: 0.0
 
 cFos_P
Compartment: nucleus
Initial amount: 0.0
 
 cJun_P
Compartment: nucleus
Initial amount: 0.0
 
 cJun_dimer
Compartment: nucleus
Initial amount: 0.0
 
 SP1
Compartment: nucleus
Initial amount: 0.0
 
 SP1_TIMP1_DNA
Compartment: nucleus
Initial amount: 0.0
 
 STAT3_nuc
Compartment: nucleus
Initial amount: 0.0
 
 STAT3_P_nuc
Compartment: nucleus
Initial amount: 0.0
 
 TIMP1_DNA
Compartment: nucleus
Initial amount: 2.0
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 IL1_IL1R
Compartment: membrane
Initial amount: 0.0
 
 IL1_IL1Ra
Compartment: membrane
Initial amount: 0.0
 
 IL1_IL1R_IRAK2
Compartment: membrane
Initial amount: 0.0
 
 IL1R
Compartment: membrane
Initial amount: 100.0
 
 IL1Ra
Compartment: membrane
Initial amount: 0.0
 
 OSM_OSMR
Compartment: membrane
Initial amount: 0.0
 
 OSM_OSMRa
Compartment: membrane
Initial amount: 0.0
 
 OSMR_SOCS3
Compartment: membrane
Initial amount: 0.0
 
 OSMR
Compartment: membrane
Initial amount: 100.0
 
 OSMRa
Compartment: membrane
Initial amount: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 ADAMTS4
Compartment: ecm
Initial amount: 0.0
 
 ADAMTS4_TIMP1
Compartment: ecm
Initial amount: 0.0
 
 ADAMTS4_TIMP3
Compartment: ecm
Initial amount: 0.0
 
 Aggrecan
Compartment: ecm
Initial amount: 0.0
 
 Aggrecan_Collagen2
Compartment: ecm
Initial amount: 100000.0
 
 AggFrag
Compartment: ecm
Initial amount: 0.0
 
 ColFrag
Compartment: ecm
Initial amount: 0.0
 
 Collagen2
Compartment: ecm
Initial amount: 0.0
 
 IL1
Compartment: ecm
Initial amount: 100.0
 
 MMP1
Compartment: ecm
Initial amount: 0.0
 
 MMP1_TIMP1
Compartment: ecm
Initial amount: 0.0
 
 MMP1_TIMP3
Compartment: ecm
Initial amount: 0.0
 
 MMP3
Compartment: ecm
Initial amount: 0.0
 
 MMP3_TIMP1
Compartment: ecm
Initial amount: 0.0
 
 MMP3_TIMP3
Compartment: ecm
Initial amount: 0.0
 
 MMP13
Compartment: ecm
Initial amount: 0.0
 
 MMP13_TIMP1
Compartment: ecm
Initial amount: 0.0
 
 MMP13_TIMP3
Compartment: ecm
Initial amount: 0.0
 
 OSM
Compartment: ecm
Initial amount: 1000.0
 
 TIMP1
Compartment: ecm
Initial amount: 200.0
 
 TIMP3
Compartment: ecm
Initial amount: 200.0
 
Global Parameters (131)
 
   kactMMP13mmp3
Value: 5.0E-8
Constant
 
   kactMMP1mat
Value: 1.0E-9
Constant
 
   kactMMP1mmp3
Value: 1.0E-8
Constant
 
   kactMMP3mat
Value: 4.0E-6
Constant
 
   kAP1activity
Value: 1.0
Constant
 
   kbincFoscJun
Value: 5.0E-5
Constant
 
   kbinIL1IL1R
Value: 1.0E-4
Constant
 
   kbinIL1IL1Ra
Value: 1.0E-4
Constant
 
   kbinIRAK2
Value: 5.0E-5
Constant
 
   kbinOSMOSMR
Value: 1.0E-5
Constant
 
   kbinOSMOSMRa
Value: 1.0E-4
Constant
 
   kbinSOCS3OSMR
Value: 0.005
Constant
 
   kbinSP1TIMP1DNA
Value: 1.0E-5
Constant
 
   kbinTRAF6
Value: 1.0E-5
Constant
 
   kcyt2nucSTAT3
Value: 0.001
Constant
 
   kdedimercJun
Value: 0.01
Constant
 
   kdegADAMTS4
Value: 5.0E-5
Constant
 
   kdegADAMTS4mRNA
Value: 1.4E-5
Constant
 
   kdegAggrecan
Value: 3.0E-8
Constant
 
   kdegcFos
Value: 2.0E-4
Constant
 
   kdegcFosmRNA
Value: 0.003
Constant
 
   kdegcJun
Value: 1.3E-4
Constant
 
   kdegcJunmRNA
Value: 0.003
Constant
 
   kdegCollagen2mmp1
Value: 5.0E-12
Constant
 
   kdegCollagen2mmp13
Value: 5.0E-11
Constant
 
   kdegDUSP16
Value: 1.3E-4
Constant
 
   kdegIL1
Value: 2.0E-4
Constant
 
   kdegMatriptase
Value: 8.0E-6
Constant
 
   kdegMKP1
Value: 1.0E-4
Constant
 
   kdegMMP1
Value: 1.0E-6
Constant
 
   kdegMMP13
Value: 1.0E-6
Constant
 
   kdegMMP13mRNA
Value: 6.4E-6
Constant
 
   kdegMMP1mRNA
Value: 6.4E-6
Constant
 
   kdegMMP3
Value: 1.0E-6
Constant
 
   kdegMMP3mRNA
Value: 6.4E-6
Constant
 
   kdegOSM
Value: 4.8E-5
Constant
 
   kdegPP4
Value: 1.0E-4
Constant
 
   kdegPTPRT
Value: 5.0E-5
Constant
 
   kdegSOCS3
Value: 8.0E-4
Constant
 
   kdegSOCS3mRNA
Value: 4.0E-4
Constant
 
   kdegSP1
Value: 2.0E-5
Constant
 
   kdegTIMP1
Value: 2.0E-5
Constant
 
   kdegTIMP1mRNA
Value: 1.4E-5
Constant
 
   kdegTIMP3
Value: 2.0E-5
Constant
 
   kdegTIMP3mRNA
Value: 1.4E-5
Constant
 
   kdephoscFos
Value: 1.0E-4
Constant
 
   kdephoscFosDUSP16
Value: 1.0E-4
Constant
 
   kdephoscJun
Value: 0.01
Constant
 
   kdephosJAK1
Value: 4.0E-4
Constant
 
   kdephosJAK1PTPRT
Value: 0.004
Constant
 
   kdephosJNK
Value: 0.001
Constant
 
   kdephosJNKDUSP16
Value: 0.001
Constant
 
   kdephosp38
Value: 0.001
Constant
 
   kdephosp38MKP1
Value: 1.0E-5
Constant
 
   kdephosSTAT3
Value: 1.0E-5
Constant
 
   kdephosSTAT3nuc
Value: 1.0E-7
Constant
 
   kdephosSTAT3nucPTPRT
Value: 5.0E-4
Constant
 
   kdephosSTAT3PTPRT
Value: 8.0E-4
Constant
 
   kdimercJun
Value: 5.0E-5
Constant
 
   kinhibADAMTS4TIMP1
Value: 3.0E-6
Constant
 
   kinhibADAMTS4TIMP3
Value: 5.0E-4
Constant
 
   kinhibMMP13TIMP1
Value: 3.0E-7
Constant
 
   kinhibMMP13TIMP3
Value: 1.0E-8
Constant
 
   kinhibMMP1TIMP1
Value: 3.0E-7
Constant
 
   kinhibMMP1TIMP3
Value: 1.0E-8
Constant
 
   kinhibMMP3TIMP1
Value: 3.0E-7
Constant
 
   kinhibMMP3TIMP3
Value: 1.0E-8
Constant
 
   kinhibTRAF6
Value: 0.5
Constant
 
   knuc2cytSTAT3
Value: 0.001
Constant
 
   kphoscFos
Value: 5.0E-7
Constant
 
   kphoscJun
Value: 1.0E-4
Constant
 
   kphosJAK1
Value: 1.0E-5
Constant
 
   kphosJNK
Value: 1.0E-4
Constant
 
   kphosp38
Value: 1.0E-4
Constant
 
   kphosSTAT3
Value: 0.005
Constant
 
   krelADAMTS4TIMP1
Value: 0.001
Constant
 
   krelADAMTS4TIMP3
Value: 0.001
Constant
 
   krelcFoscJun
Value: 4.0E-5
Constant
 
   krelIL1IL1R
Value: 0.001
Constant
 
   krelIL1IL1Ra
Value: 1.0E-4
Constant
 
   krelIRAK2
Value: 0.001
Constant
 
   krelMMP1
Value: 0.001
Constant
 
   krelMMP13
Value: 0.001
Constant
 
   krelMMP13TIMP3
Value: 0.001
Constant
 
   krelMMP1TIMP3
Value: 0.001
Constant
 
   krelMMP3
Value: 0.001
Constant
 
   krelMMP3TIMP3
Value: 0.001
Constant
 
   krelOSMOSMR
Value: 1.0E-5
Constant
 
   krelOSMOSMRa
Value: 1.0E-5
Constant
 
   krelSOCS3OSMR
Value: 1.0E-5
Constant
 
   krelSP1TIMP1DNA
Value: 5.0E-6
Constant
 
   krelTRAF6
Value: 1.0E-4
Constant
 
   krelTRAF6PP4
Value: 1.0E-6
Constant
 
   ksynADAMTS4
Value: 5.0E-4
Constant
 
   ksynADAMTS4mRNA
Value: 5.0E-4
Constant
 
   ksynADAMTS4mRNAcJun
Value: 4.0E-6
Constant
 
   ksynbasalcJunmRNA
Value: 0.015
Constant
 
   ksynbasalTIMP1mRNA
Value: 1.4E-4
Constant
 
   ksynbasalTIMP3mRNA
Value: 2.8E-4
Constant
 
   ksyncFos
Value: 0.001
Constant
 
   ksyncFosmRNA
Value: 5.0E-6
Constant
 
   ksyncFosmRNAStat3
Value: 0.05
Constant
 
   ksyncJun
Value: 0.0026
Constant
 
   ksyncJunmRNA
Value: 0.0125
Constant
 
   ksyncJunmRNAcJun
Value: 0.005
Constant
 
   ksynDUSP16
Value: 0.005
Constant
 
   ksynDUSP16cJun
Value: 2.0E-4
Constant
 
   ksynMatriptase
Value: 9.0E-10
Constant
 
   ksynMKP1
Value: 2.5E-5
Constant
 
   ksynMKP1cJun
Value: 1.0E-6
Constant
 
   ksynMMP1
Value: 1.5E-4
Constant
 
   ksynMMP13
Value: 1.5E-5
Constant
 
   ksynMMP13mRNA
Value: 5.0E-4
Constant
 
   ksynMMP13mRNAcJun
Value: 2.0E-5
Constant
 
   ksynMMP1mRNA
Value: 0.005
Constant
 
   ksynMMP1mRNAcJun
Value: 2.0E-4
Constant
 
   ksynMMP3
Value: 3.0E-5
Constant
 
   ksynMMP3mRNA
Value: 0.005
Constant
 
   ksynMMP3mRNAcJun
Value: 2.0E-4
Constant
 
   ksynPP4
Value: 0.005
Constant
 
   ksynPP4cJun
Value: 2.0E-4
Constant
 
   ksynPTPRT
Value: 1.0E-4
Constant
 
   ksynSOCS3
Value: 0.001
Constant
 
   ksynSOCS3mRNA
Value: 0.006
Constant
 
   ksynSP1
Value: 2.0E-5
Constant
 
   ksynTIMP1
Value: 2.0E-4
Constant
 
   ksynTIMP1mRNA
Value: 5.0E-7
Constant
 
   ksynTIMP1mRNAStat3
Value: 4.0E-5
Constant
 
   ksynTIMP3
Value: 4.0E-4
Constant
 
   ksynTIMP3mRNA
Value: 5.0E-7
Constant
 
   ksynTIMP3mRNAStat3
Value: 4.0E-5
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000504

Curator's comment: (updated: 10 Jan 2014 16:53:54 GMT)

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.

spacer
spacer