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BIOMD0000000560 - Hui2014 - Age-related changes in articular cartilage

 

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Reference Publication
Publication ID: 25475114
Hui W, Young DA, Rowan AD, Xu X, Cawston TE, Proctor CJ.
Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage.
Ann. Rheum. Dis. 2014 Dec; :
MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.  [more]
Model
Original Model: AgeingCartilage
Submitter: Carole Proctor
Submission ID: MODEL1402200004
Submission Date: 20 Feb 2014 13:27:41 UTC
Last Modification Date: 08 Apr 2016 18:51:50 UTC
Creation Date: 05 Dec 2014 17:02:43 UTC
Encoders:  Vijayalakshmi Chelliah
   Carole Proctor
set #1
bqbiol:occursIn FMA Knee joint
set #2
bqbiol:isVersionOf Gene Ontology cartilage development
Gene Ontology age-dependent response to oxidative stress involved in replicative cell aging
set #3
bqbiol:hasTaxon Taxonomy Mus musculus
set #4
bqbiol:hasProperty Human Disease Ontology osteoarthritis
Notes
Hui2014 - Age-related changes in articular cartilage

This model is described in the article:

Wang Hui1, David A Young1, Andrew D Rowan1, Xin Xu2, Tim E Cawston1, Carole J Proctor1,3
Annals of the Rheumatic Diseases

Abstract:

Objective: To use a computational approach to investigate the cellular and extracellular matrix changes that occur with age in the knee joints of mice. Methods: Knee joints from an inbred C57/BL1/6 (ICRFa) mouse colony were harvested at 3–30?months of age. Sections were stained with H&E, Safranin-O, Picro-sirius red and antibodies to matrix metalloproteinase-13 (MMP-13), nitrotyrosine, LC-3B, Bcl-2, and cleaved type II collagen used for immunohistochemistry. Based on this and other data from the literature, a computer simulation model was built using the Systems Biology Markup Language using an iterative approach of data analysis and modelling. Individual parameters were subsequently altered to assess their effect on the model. Results: A progressive loss of cartilage matrix occurred with age. Nitrotyrosine, MMP-13 and anaplastic lymphoma kinase (ALK1) staining in cartilage increased with age with a concomitant decrease in LC-3B and Bcl-2. Stochastic simulations from the computational model showed a good agreement with these data, once transforming growth factor-? signalling via ALK1/ALK5 receptors was included. Oxidative stress and the interleukin 1 pathway were identified as key factors in driving the cartilage breakdown associated with ageing. Conclusions: A progressive loss of cartilage matrix and cellularity occurs with age. This is accompanied with increased levels of oxidative stress, apoptosis and MMP-13 and a decrease in chondrocyte autophagy. These changes explain the marked predisposition of joints to develop osteoarthritis with age. Computational modelling provides useful insights into the underlying mechanisms involved in age-related changes in musculoskeletal tissues.

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: 25475114 Submission Date: 20 Feb 2014 13:27:41 UTC Last Modification Date: 08 Apr 2016 18:51:50 UTC Creation Date: 05 Dec 2014 17:02:43 UTC
Mathematical expressions
Reactions
CaspaseActivation CaspaseActivationByBeclin_I CaspaseActivationBy_p38 CaspaseInactivation1
InhibitCaspase2 InhibitCaspase3 ActivateLysosome InhibitLysosome
Bcl2Synthesis Bcl2Degradation Bcl2DegradationStressInduced Bcl2DegradationCaspaseInduced
Bax_Bcl2Binding Bax_Bcl2Release Bcl2_BeclinBinding Bcl2_BeclinRelease
Bcl2_Beclin_I_Binding Bcl2_Beclin_I_Release BeclinInactivation BeclinInactivationByCaspase
BeclinBindingToBax_Bcl2 BeclinIBindingToBax_Bcl2 BaxBindingToBcl2_Beclin BaxBindingToBcl2_BeclinI
BaxDissociation_Bax_Bcl2_Beclin BaxDissociation_Bax_Bcl2_Beclin_I BeclinDissociation_Bax_Bcl2_Beclin Beclin_I_Dissociation_Bax_Bcl2_Beclin
ROS_generation ROS_removal Protein_Damage_by_ROS Removal_DamP_by_Autophagy
Production_of_AGEproducts RAGE_activation ROS_production_by_RAGE IkB_degradation_via_ROS
IkB_degradation_via_IL1 NFkB_inactivation RAGE_inactivation RAGE_upregulation_byNFkB
IL1_production IL1_degradation IkB_production MMP13_production
MMP13_removal MMP2_production MMP_activation MMP2_degradation
ADAMTS5_production ADAMTS5_removal Aggrecan_degradation Collagen_degradation
ROS_production_by_DamP Protein_synthesis SOD_synthesis SOD_degradation
ROS_removal_by_SOD p38_phosphorylation p38_phosphorylation_via_ROS p38_dephosphorylation
NFkB_activation NFkB_dephosphorylation ROS_production_by_p38_P Lysosome_damage_by_ROS
IntegrinActivationByMechanicalStress IntegrinInactivation Alk5Synthesis TgfbActivationByIntegrin
TgfbActivationByMMP2 TgfbInactivation Alk5Dimerisation Alk5Dedimerisation
Alk1Alk5Binding Alk1Alk5Release TgfbReceptorBindingAlk5 TgfbReceptorRelease
Tgfb_Alk5_BindingSmad7 Tgfb_Alk5_Smad7Release Alk5_Smad7Degradation TgfbReceptorBindingAlk1
TgfbAlk1Release Smad2Phosphorylation Smad2Smad4Binding Smad2PSmad4Release
Smad2DephosphorylationNuc Smad7Synthesis Sox9Activation Sox9Inactivation
Sox9BasalTranscription Sox9EnhancedTranscription Sox9mRNA_Degradation Sox9Translation
Sox9Degradation Collagen2EnhancedTranscriptionBySox9 Collagen2TranscriptionBySmad2Smad4 Col2mRNA_Degradation
Collagen2Translation AggrecanEnhancedTranscription AcanmRNA_Degradation AggrecanTranslation
AggrecanCollagen2Binding Runx2_InhibitionBySmad2 Alk5Degradation Smad1Activation
Smad1Dephosphorylation Smad1DephosphorylationViaSmad7 Smad1Smad4Binding Smad1Smad4Release
Runx2ActivationBySmad1 MMP13InductionByRunx2 Alk1Synthesis Alk1Degradation
MMP13Activation Tgfb_Alk1_Alk5_BindingSmad7 Tgfb_Alk1_Alk5_Smad7Release Alk1_Smad7Degradation
Smad7Degradation      
Physical entities
Compartments Species
cell AcanmRNA ADAMTS5 AGEprod
Alk1 Alk1_Alk5 Alk5
Alk5_dimer Bax Bax_Bcl2
Bax_Bcl2_Beclin Bax_Bcl2_Beclin_I Bcl2
Bcl2_Beclin Bcl2_Beclin_I Beclin
Beclin_I Caspase_A Caspase_I
Col2mRNA DamP IkB
IkB_NFkB IL1 Lys_A
Lys_I MMP13 MMP2
NatP NFkB NFkB_P
p38 p38_P proMMP13
proMMP2 RAGE ROS
Runx2_A Runx2_I Smad1
Smad1_P Smad1_P_Smad4 Smad2
Smad2_P Smad2_P_Smad4 Smad4
Smad7 SOD Sox9
Sox9_A Sox9mRNA Tgfb_A
Tgfb_Alk1_Alk5 Tgfb_Alk1_Alk5_Smad7 Tgfb_Alk5_dimer
Tgfb_Alk5_dimer_Smad7 Sink Source
     
nucleus      
membrane      
ecm AggFrag Aggrecan Aggrecan_Collagen2
ColFrag Collagen2 Integrin
Tgfb_I IntegrinCount  
Global parameters
kactCasp kactCaspBecI kactCaspp38 kactIntegrin
kactLys kactMMP13 kactMMP2 kactNFkB
kactRAGE kactRunx2 kactSox9 kactTgfbIntegrin
kactTgfbMMP2 kbinAggrecanCollagen2 kbinAlk1Alk5 kbinBaxBcl2
kbinBaxToBcl2Bec kbinBcl2Beclin kbinBecToBaxBcl2 kbinSmad1Smad4
kbinSmad2Smad4 kbinSmad7Alk1 kbinSmad7Alk5 kbinTgfbAlk1
kbinTgfbAlk5 kdamLys kdamNatP kdedimerAlk5
kdegAcanmRNA kdegADAMTS5 kdegAggrecan kdegAlk1
kdegAlk5 kdegBcl2 kdegBcl2Casp kdegBcl2ROS
kdegCol2mRNA kdegCollagen kdegDamP kdegIkB
kdegIL1 kdegMMP13 kdegMMP2 kdegSmad7
kdegSmad7Alk1 kdegSmad7Alk5 kdegSOD kdegSox9
kdegSox9mRNA kdegTgfb kdephosNFkB kdephosp38
kdephosSmad1 kdephosSmad1Smad7 kdephosSmad2 kdimerAlk5
kgenROS kgenROSbyDamP kgenROSbyp38 kgenROSbyRAGE
kinactBec kinactBecCasp kinactCasp kinactCaspBcl2
kinactIntegrin kinactNFkB kinactRAGE kinactRunx2
kinactSox9 kinactTgfb kinhibLys kphosNFkB
kphosp38 kphosp38ROS kphosSmad1 kphosSmad2
kprodAGE krelAlk1Alk5 krelBaxBcl2 krelBaxBcl2Bec
krelBcl2Beclin krelBecBaxBcl2 krelSmad1Smad4 krelSmad2Smad4
krelSmad7Alk1 krelSmad7Alk5 krelTgfbAlk1 krelTgfbAlk5
kremROS kremROSbySOD ksynAcanmRNA ksynAcanmRNASox9A
ksynADAMTS5 ksynAggrecan ksynAlk1 ksynAlk5
ksynBcl2 ksynCol2 ksynCol2mRNA ksynCol2mRNASmad
ksynCol2mRNASox9A ksynIkB ksynIL1 ksynMMP13
ksynMMP13Runx2 ksynMMP2 ksynNatP ksynRAGE
ksynSmad7 ksynSOD ksynSox9 ksynSox9mRNA
ksynSox9mRNASox9A      
Reactions (117)
 
 CaspaseActivation [Caspase_I] + [Bax] → [Caspase_A] + [Bax];   {Caspase_I} , {Bax}
 
 CaspaseActivationByBeclin_I [Caspase_I] + [Beclin_I] → [Caspase_A] + [Beclin_I];   {Caspase_I} , {Beclin_I}
 
 CaspaseActivationBy_p38 [Caspase_I] + [p38_P] → [Caspase_A] + [p38_P];   {Caspase_I} , {p38_P}
 
 CaspaseInactivation1 [Caspase_A] → [Caspase_I];   {Caspase_A}
 
 InhibitCaspase2 [Caspase_A] + [Bcl2_Beclin] → [Caspase_I] + [Bcl2_Beclin];   {Caspase_A} , {Bcl2_Beclin}
 
 InhibitCaspase3 [Caspase_A] + [Bcl2] → [Caspase_I] + [Bcl2];   {Caspase_A} , {Bcl2}
 
 ActivateLysosome [Lys_I] + [Beclin] → [Lys_A] + [Beclin];   {Lys_I} , {Beclin}
 
 InhibitLysosome [Lys_A] → [Lys_I];   {Lys_A}
 
 Bcl2Synthesis [Source] → [Bcl2];   {Source}
 
 Bcl2Degradation [Bcl2] → [Sink];   {Bcl2}
 
 Bcl2DegradationStressInduced [Bcl2] + [ROS] → [Sink] + [ROS];   {Bcl2} , {ROS}
 
 Bcl2DegradationCaspaseInduced [Bcl2] + [Caspase_A] → [Sink] + [Caspase_A];   {Bcl2} , {Caspase_A}
 
 Bax_Bcl2Binding [Bax] + [Bcl2] → [Bax_Bcl2];   {Bax} , {Bcl2}
 
 Bax_Bcl2Release [Bax_Bcl2] → [Bax] + [Bcl2];   {Bax_Bcl2}
 
 Bcl2_BeclinBinding [Bcl2] + [Beclin] → [Bcl2_Beclin];   {Bcl2} , {Beclin}
 
 Bcl2_BeclinRelease [Bcl2_Beclin] → [Bcl2] + [Beclin];   {Bcl2_Beclin}
 
 Bcl2_Beclin_I_Binding [Bcl2] + [Beclin_I] → [Bcl2_Beclin_I];   {Bcl2} , {Beclin_I}
 
 Bcl2_Beclin_I_Release [Bcl2_Beclin_I] → [Bcl2] + [Beclin_I];   {Bcl2_Beclin_I}
 
 BeclinInactivation [Beclin] → [Beclin_I];   {Beclin}
 
 BeclinInactivationByCaspase [Beclin] + [Caspase_A] → [Beclin_I] + [Caspase_A];   {Beclin} , {Caspase_A}
 
 BeclinBindingToBax_Bcl2 [Beclin] + [Bax_Bcl2] → [Bax_Bcl2_Beclin];   {Beclin} , {Bax_Bcl2}
 
 BeclinIBindingToBax_Bcl2 [Beclin_I] + [Bax_Bcl2] → [Bax_Bcl2_Beclin_I];   {Beclin_I} , {Bax_Bcl2}
 
 BaxBindingToBcl2_Beclin [Bax] + [Bcl2_Beclin] → [Bax_Bcl2_Beclin];   {Bax} , {Bcl2_Beclin}
 
 BaxBindingToBcl2_BeclinI [Bax] + [Bcl2_Beclin_I] → [Bax_Bcl2_Beclin_I];   {Bax} , {Bcl2_Beclin_I}
 
 BaxDissociation_Bax_Bcl2_Beclin [Bax_Bcl2_Beclin] → [Bax] + [Bcl2_Beclin];   {Bax_Bcl2_Beclin}
 
 BaxDissociation_Bax_Bcl2_Beclin_I [Bax_Bcl2_Beclin_I] → [Bax] + [Bcl2_Beclin_I];   {Bax_Bcl2_Beclin_I}
 
 BeclinDissociation_Bax_Bcl2_Beclin [Bax_Bcl2_Beclin] → [Beclin] + [Bax_Bcl2];   {Bax_Bcl2_Beclin}
 
 Beclin_I_Dissociation_Bax_Bcl2_Beclin [Bax_Bcl2_Beclin_I] → [Beclin_I] + [Bax_Bcl2];   {Bax_Bcl2_Beclin_I}
 
 ROS_generation [Source] → [ROS];   {Source}
 
 ROS_removal [ROS] → [Sink];   {ROS}
 
 Protein_Damage_by_ROS [NatP] + [ROS] → [DamP] + [ROS];   {NatP} , {ROS}
 
 Removal_DamP_by_Autophagy [DamP] + [Lys_A] → [Lys_A];   {DamP} , {Lys_A}
 
 Production_of_AGEproducts [Source] → [AGEprod];   {Source}
 
 RAGE_activation [AGEprod] → [AGEprod] + [RAGE];   {AGEprod}
 
 ROS_production_by_RAGE [RAGE] → [RAGE] + [ROS];   {RAGE}
 
 IkB_degradation_via_ROS [ROS] + [IkB_NFkB] → [ROS] + [NFkB];   {ROS} , {IkB_NFkB}
 
 IkB_degradation_via_IL1 [IL1] + [IkB_NFkB] → [IL1] + [NFkB];   {IL1} , {IkB_NFkB}
 
 NFkB_inactivation [NFkB] + [IkB] → [IkB_NFkB];   {NFkB} , {IkB}
 
 RAGE_inactivation [RAGE] → [Sink];   {RAGE}
 
 RAGE_upregulation_byNFkB [NFkB_P] → [NFkB_P] + [RAGE];   {NFkB_P}
 
 IL1_production [NFkB_P] → [NFkB_P] + [IL1];   {NFkB_P}
 
 IL1_degradation [IL1] → [Sink];   {IL1}
 
 IkB_production [NFkB_P] → [NFkB_P] + [IkB];   {NFkB_P}
 
 MMP13_production [IL1] → [IL1] + [proMMP13];   {IL1}
 
 MMP13_removal [MMP13] → [Sink];   {MMP13}
 
 MMP2_production [IL1] → [IL1] + [proMMP2];   {IL1}
 
 MMP_activation [proMMP2] → [MMP2];   {proMMP2}
 
 MMP2_degradation [MMP2] → [Sink];   {MMP2}
 
 ADAMTS5_production [IL1] → [IL1] + [ADAMTS5];   {IL1}
 
 ADAMTS5_removal [ADAMTS5] → [Sink];   {ADAMTS5}
 
 Aggrecan_degradation [Aggrecan_Collagen2] + [ADAMTS5] → [Collagen2] + [ADAMTS5] + [AggFrag];   {Aggrecan_Collagen2} , {ADAMTS5}
 
 Collagen_degradation [Collagen2] + [MMP13] → [MMP13] + [ColFrag];   {Collagen2} , {MMP13}
 
 ROS_production_by_DamP [DamP] → [DamP] + [ROS];   {DamP}
 
 Protein_synthesis [Source] → [NatP];   {Source}
 
 SOD_synthesis [NFkB_P] → [NFkB_P] + [SOD];   {NFkB_P}
 
 SOD_degradation [SOD] → [Sink];   {SOD}
 
 ROS_removal_by_SOD [ROS] + [SOD] → [SOD];   {SOD} , {ROS}
 
 p38_phosphorylation [p38] + [IL1] → [p38_P] + [IL1];   {p38} , {IL1}
 
 p38_phosphorylation_via_ROS [p38] + [ROS] → [p38_P] + [ROS];   {p38} , {ROS}
 
 p38_dephosphorylation [p38_P] → [p38];   {p38_P}
 
 NFkB_activation [NFkB] + [p38_P] → [NFkB_P] + [p38_P];   {NFkB} , {p38_P}
 
 NFkB_dephosphorylation [NFkB_P] → [NFkB];   {NFkB_P}
 
 ROS_production_by_p38_P [p38_P] → [p38_P] + [ROS];   {p38_P}
 
 Lysosome_damage_by_ROS [Lys_A] + [ROS] → [Lys_I] + [ROS];   {Lys_A} , {ROS}
 
 IntegrinActivationByMechanicalStress [Source] → [Integrin] + [IntegrinCount];   {Source}
 
 IntegrinInactivation [Integrin] → [Sink];   {Integrin}
 
 Alk5Synthesis [Source] → [Alk5];   {Source}
 
 TgfbActivationByIntegrin [Tgfb_I] + [Integrin] → [Tgfb_A] + [Integrin];   {Tgfb_I} , {Integrin}
 
 TgfbActivationByMMP2 [Tgfb_I] + [MMP2] → [Tgfb_A] + [MMP2];   {Tgfb_I} , {MMP2}
 
 TgfbInactivation [Tgfb_A] → [Tgfb_I];   {Tgfb_A}
 
 Alk5Dimerisation 2.0 × [Alk5] → [Alk5_dimer];   {Alk5}
 
 Alk5Dedimerisation [Alk5_dimer] → 2.0 × [Alk5];   {Alk5_dimer}
 
 Alk1Alk5Binding [Alk1] + [Alk5] → [Alk1_Alk5];   {Alk1} , {Alk5}
 
 Alk1Alk5Release [Alk1_Alk5] → [Alk1] + [Alk5];   {Alk1_Alk5}
 
 TgfbReceptorBindingAlk5 [Tgfb_A] + [Alk5_dimer] → [Tgfb_Alk5_dimer];   {Tgfb_A} , {Alk5_dimer}
 
 TgfbReceptorRelease [Tgfb_Alk5_dimer] → [Tgfb_A] + [Alk5_dimer];   {Tgfb_Alk5_dimer}
 
 Tgfb_Alk5_BindingSmad7 [Tgfb_Alk5_dimer] + [Smad7] → [Tgfb_Alk5_dimer_Smad7];   {Tgfb_Alk5_dimer} , {Smad7}
 
 Tgfb_Alk5_Smad7Release [Tgfb_Alk5_dimer_Smad7] → [Tgfb_Alk5_dimer] + [Smad7];   {Tgfb_Alk5_dimer_Smad7}
 
 Alk5_Smad7Degradation [Tgfb_Alk5_dimer_Smad7] → [Tgfb_I];   {Tgfb_Alk5_dimer_Smad7}
 
 TgfbReceptorBindingAlk1 [Tgfb_A] + [Alk1_Alk5] → [Tgfb_Alk1_Alk5];   {Tgfb_A} , {Alk1_Alk5}
 
 TgfbAlk1Release [Tgfb_Alk1_Alk5] → [Tgfb_A] + [Alk1_Alk5];   {Tgfb_Alk1_Alk5}
 
 Smad2Phosphorylation [Tgfb_Alk5_dimer] + [Smad2] → [Tgfb_Alk5_dimer] + [Smad2_P];   {Tgfb_Alk5_dimer} , {Smad2}
 
 Smad2Smad4Binding [Smad2_P] + [Smad4] → [Smad2_P_Smad4];   {Smad2_P} , {Smad4}
 
 Smad2PSmad4Release [Smad2_P_Smad4] → [Smad2_P] + [Smad4];   {Smad2_P_Smad4}
 
 Smad2DephosphorylationNuc [Smad2_P] → [Smad2];   {Smad2_P}
 
 Smad7Synthesis [Smad2_P_Smad4] → [Smad2_P_Smad4] + [Smad7];   {Smad2_P_Smad4}
 
 Sox9Activation [Smad2_P_Smad4] + [Sox9] → [Smad2_P_Smad4] + [Sox9_A];   {Smad2_P_Smad4} , {Sox9}
 
 Sox9Inactivation [Sox9_A] → [Sox9];   {Sox9_A}
 
 Sox9BasalTranscription [Source] → [Sox9mRNA];   {Source}
 
 Sox9EnhancedTranscription [Sox9_A] → [Sox9_A] + [Sox9mRNA];   {Sox9_A}
 
 Sox9mRNA_Degradation [Sox9mRNA] → [Sink];   {Sox9mRNA}
 
 Sox9Translation [Sox9mRNA] → [Sox9mRNA] + [Sox9];   {Sox9mRNA}
 
 Sox9Degradation [Sox9] → [Sink];   {Sox9}
 
 Collagen2EnhancedTranscriptionBySox9 [Sox9_A] → [Sox9_A] + [Col2mRNA];   {Sox9_A}
 
 Collagen2TranscriptionBySmad2Smad4 [Smad2_P_Smad4] → [Smad2_P_Smad4] + [Col2mRNA];   {Smad2_P_Smad4}
 
 Col2mRNA_Degradation [Col2mRNA] → [Sink];   {Col2mRNA}
 
 Collagen2Translation [Col2mRNA] → [Col2mRNA] + [Collagen2];   {Col2mRNA}
 
 AggrecanEnhancedTranscription [Sox9_A] → [Sox9_A] + [AcanmRNA];   {Sox9_A}
 
 AcanmRNA_Degradation [AcanmRNA] → [Sink];   {AcanmRNA}
 
 AggrecanTranslation [AcanmRNA] → [AcanmRNA] + [Aggrecan];   {AcanmRNA}
 
 AggrecanCollagen2Binding [Aggrecan] + [Collagen2] → [Aggrecan_Collagen2];   {Aggrecan} , {Collagen2}
 
 Runx2_InhibitionBySmad2 [Runx2_A] + [Smad2_P_Smad4] → [Runx2_I] + [Smad2_P_Smad4];   {Runx2_A} , {Smad2_P_Smad4}
 
 Alk5Degradation [Alk5] → [Sink];   {Alk5}
 
 Smad1Activation [Tgfb_Alk1_Alk5] + [Smad1] → [Tgfb_Alk1_Alk5] + [Smad1_P];   {Tgfb_Alk1_Alk5} , {Smad1}
 
 Smad1Dephosphorylation [Smad1_P] → [Smad1];   {Smad1_P}
 
 Smad1DephosphorylationViaSmad7 [Smad1_P] + [Smad7] → [Smad1] + [Smad7];   {Smad1_P} , {Smad7}
 
 Smad1Smad4Binding [Smad1_P] + [Smad4] → [Smad1_P_Smad4];   {Smad1_P} , {Smad4}
 
 Smad1Smad4Release [Smad1_P_Smad4] → [Smad1_P] + [Smad4];   {Smad1_P_Smad4}
 
 Runx2ActivationBySmad1 [Runx2_I] + [Smad1_P_Smad4] → [Runx2_A] + [Smad1_P_Smad4];   {Runx2_I} , {Smad1_P_Smad4}
 
 MMP13InductionByRunx2 [Runx2_A] → [proMMP13] + [Runx2_A];   {Runx2_A}
 
 Alk1Synthesis [Source] → [Alk1];   {Source}
 
 Alk1Degradation [Alk1] → [Sink];   {Alk1}
 
 MMP13Activation [proMMP13] → [MMP13];   {proMMP13}
 
 Tgfb_Alk1_Alk5_BindingSmad7 [Tgfb_Alk1_Alk5] + [Smad7] → [Tgfb_Alk1_Alk5_Smad7];   {Tgfb_Alk1_Alk5} , {Smad7}
 
 Tgfb_Alk1_Alk5_Smad7Release [Tgfb_Alk1_Alk5_Smad7] → [Tgfb_Alk1_Alk5] + [Smad7];   {Tgfb_Alk1_Alk5_Smad7}
 
 Alk1_Smad7Degradation [Tgfb_Alk1_Alk5_Smad7] → [Tgfb_I];   {Tgfb_Alk1_Alk5_Smad7}
 
 Smad7Degradation [Smad7] → [Sink];   {Smad7}
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 AcanmRNA
Compartment: cell
Initial amount: 0.0
 
 ADAMTS5
Compartment: cell
Initial amount: 0.0
 
   AGEprod
Compartment: cell
Initial amount: 0.0
 
 Alk1
Compartment: cell
Initial amount: 500.0
 
 Alk1_Alk5
Compartment: cell
Initial amount: 0.0
 
 Alk5
Compartment: cell
Initial amount: 500.0
 
 Alk5_dimer
Compartment: cell
Initial amount: 0.0
 
 Bax
Compartment: cell
Initial amount: 0.0
 
 Bax_Bcl2
Compartment: cell
Initial amount: 90.0
 
 Bax_Bcl2_Beclin
Compartment: cell
Initial amount: 10.0
 
 Bax_Bcl2_Beclin_I
Compartment: cell
Initial amount: 0.0
 
 Bcl2
Compartment: cell
Initial amount: 30.0
 
 Bcl2_Beclin
Compartment: cell
Initial amount: 25.0
 
 Bcl2_Beclin_I
Compartment: cell
Initial amount: 0.0
 
 Beclin
Compartment: cell
Initial amount: 75.0
 
 Beclin_I
Compartment: cell
Initial amount: 0.0
 
 Caspase_A
Compartment: cell
Initial amount: 0.0
 
 Caspase_I
Compartment: cell
Initial amount: 100.0
 
 Col2mRNA
Compartment: cell
Initial amount: 0.0
 
   DamP
Compartment: cell
Initial amount: 0.0
 
 IkB
Compartment: cell
Initial amount: 0.0
 
 IkB_NFkB
Compartment: cell
Initial amount: 100.0
 
 IL1
Compartment: cell
Initial amount: 0.0
 
 Lys_A
Compartment: cell
Initial amount: 40.0
 
 Lys_I
Compartment: cell
Initial amount: 360.0
 
 MMP13
Compartment: cell
Initial amount: 0.0
 
 MMP2
Compartment: cell
Initial amount: 0.0
 
   NatP
Compartment: cell
Initial amount: 1500.0
Constant
 
 NFkB
Compartment: cell
Initial amount: 0.0
 
 NFkB_P
Compartment: cell
Initial amount: 0.0
 
 p38
Compartment: cell
Initial amount: 100.0
 
 p38_P
Compartment: cell
Initial amount: 0.0
 
 proMMP13
Compartment: cell
Initial amount: 0.0
 
 proMMP2
Compartment: cell
Initial amount: 0.0
 
 RAGE
Compartment: cell
Initial amount: 0.0
 
 ROS
Compartment: cell
Initial amount: 2.0
 
 Runx2_A
Compartment: cell
Initial amount: 0.0
 
 Runx2_I
Compartment: cell
Initial amount: 100.0
 
 Smad1
Compartment: cell
Initial amount: 600.0
 
 Smad1_P
Compartment: cell
Initial amount: 0.0
 
 Smad1_P_Smad4
Compartment: cell
Initial amount: 0.0
 
 Smad2
Compartment: cell
Initial amount: 600.0
 
 Smad2_P
Compartment: cell
Initial amount: 0.0
 
 Smad2_P_Smad4
Compartment: cell
Initial amount: 0.0
 
 Smad4
Compartment: cell
Initial amount: 600.0
 
 Smad7
Compartment: cell
Initial amount: 0.0
 
 SOD
Compartment: cell
Initial amount: 2.0
 
 Sox9
Compartment: cell
Initial amount: 100.0
 
 Sox9_A
Compartment: cell
Initial amount: 0.0
 
 Sox9mRNA
Compartment: cell
Initial amount: 10.0
 
 Tgfb_A
Compartment: cell
Initial amount: 0.0
 
 Tgfb_Alk1_Alk5
Compartment: cell
Initial amount: 0.0
 
 Tgfb_Alk1_Alk5_Smad7
Compartment: cell
Initial amount: 0.0
 
 Tgfb_Alk5_dimer
Compartment: cell
Initial amount: 0.0
 
 Tgfb_Alk5_dimer_Smad7
Compartment: cell
Initial amount: 0.0
 
 Sink
Compartment: cell
Initial amount: 0.0
Constant
 
 Source
Compartment: cell
Initial amount: 1.0
Constant
 
  Spatial dimensions: 3.0  Compartment size: 1.0
  Spatial dimensions: 3.0  Compartment size: 1.0
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 AggFrag
Compartment: ecm
Initial amount: 0.0
 
 Aggrecan
Compartment: ecm
Initial amount: 0.0
 
 Aggrecan_Collagen2
Compartment: ecm
Initial amount: 1000.0
 
 ColFrag
Compartment: ecm
Initial amount: 0.0
 
 Collagen2
Compartment: ecm
Initial amount: 0.0
 
 Integrin
Compartment: ecm
Initial amount: 0.0
 
 Tgfb_I
Compartment: ecm
Initial amount: 200.0
 
 IntegrinCount
Compartment: ecm
Initial amount: 0.0
 
Global Parameters (113)
 
   kactCasp
Value: 1.0E-7
Constant
 
   kactCaspBecI
Value: 8.3E-7
Constant
 
   kactCaspp38
Value: 8.0E-7
Constant
 
   kactIntegrin
Value: 4.0E-7
Constant
 
   kactLys
Value: 1.0E-8
Constant
 
   kactMMP13
Value: 1.0E-4
Constant
 
   kactMMP2
Value: 1.0E-7
Constant
 
   kactNFkB
Value: 1.0E-4
Constant
 
   kactRAGE
Value: 0.001
Constant
 
   kactRunx2
Value: 0.001
Constant
 
   kactSox9
Value: 5.0E-6
Constant
 
   kactTgfbIntegrin
Value: 0.001
Constant
 
   kactTgfbMMP2
Value: 1.0E-7
Constant
 
   kbinAggrecanCollagen2
Value: 1.0E-4
Constant
 
   kbinAlk1Alk5
Value: 5.0E-5
Constant
 
   kbinBaxBcl2
Value: 1.67
Constant
 
   kbinBaxToBcl2Bec
Value: 1.67E-4
Constant
 
   kbinBcl2Beclin
Value: 7.5E-5
Constant
 
   kbinBecToBaxBcl2
Value: 1.67E-5
Constant
 
   kbinSmad1Smad4
Value: 5.0E-5
Constant
 
   kbinSmad2Smad4
Value: 1.0E-4
Constant
 
   kbinSmad7Alk1
Value: 0.5
Constant
 
   kbinSmad7Alk5
Value: 2.0E-5
Constant
 
   kbinTgfbAlk1
Value: 2.0E-5
Constant
 
   kbinTgfbAlk5
Value: 3.0E-5
Constant
 
   kdamLys
Value: 5.0E-6
Constant
 
   kdamNatP
Value: 8.0E-6
Constant
 
   kdedimerAlk5
Value: 0.001
Constant
 
   kdegAcanmRNA
Value: 9.0E-6
Constant
 
   kdegADAMTS5
Value: 5.0E-5
Constant
 
   kdegAggrecan
Value: 1.0E-9
Constant
 
   kdegAlk1
Value: 1.2E-8
Constant
 
   kdegAlk5
Value: 4.0E-7
Constant
 
   kdegBcl2
Value: 1.67E-4
Constant
 
   kdegBcl2Casp
Value: 0.00167
Constant
 
   kdegBcl2ROS
Value: 0.00167
Constant
 
   kdegCol2mRNA
Value: 1.07E-5
Constant
 
   kdegCollagen
Value: 1.0E-8
Constant
 
   kdegDamP
Value: 4.0E-5
Constant
 
   kdegIkB
Value: 1.0E-6
Constant
 
   kdegIL1
Value: 0.005
Constant
 
   kdegMMP13
Value: 6.4E-6
Constant
 
   kdegMMP2
Value: 6.4E-6
Constant
 
   kdegSmad7
Value: 0.005
Constant
 
   kdegSmad7Alk1
Value: 5.0E-6
Constant
 
   kdegSmad7Alk5
Value: 1.0E-5
Constant
 
   kdegSOD
Value: 0.001
Constant
 
   kdegSox9
Value: 4.8E-5
Constant
 
   kdegSox9mRNA
Value: 1.0E-4
Constant
 
   kdegTgfb
Value: 0.00578
Constant
 
   kdephosNFkB
Value: 0.01
Constant
 
   kdephosp38
Value: 0.01
Constant
 
   kdephosSmad1
Value: 5.0E-4
Constant
 
   kdephosSmad1Smad7
Value: 6.0E-4
Constant
 
   kdephosSmad2
Value: 0.006
Constant
 
   kdimerAlk5
Value: 2.0E-4
Constant
 
   kgenROS
Value: 5.0E-4
Constant
 
   kgenROSbyDamP
Value: 1.0E-4
Constant
 
   kgenROSbyp38
Value: 1.0E-4
Constant
 
   kgenROSbyRAGE
Value: 4.0E-4
Constant
 
   kinactBec
Value: 5.0E-10
Constant
 
   kinactBecCasp
Value: 1.0E-8
Constant
 
   kinactCasp
Value: 3.0E-4
Constant
 
   kinactCaspBcl2
Value: 3.0E-4
Constant
 
   kinactIntegrin
Value: 5.0E-4
Constant
 
   kinactNFkB
Value: 0.1
Constant
 
   kinactRAGE
Value: 0.001
Constant
 
   kinactRunx2
Value: 5.0E-4
Constant
 
   kinactSox9
Value: 0.0015
Constant
 
   kinactTgfb
Value: 0.05
Constant
 
   kinhibLys
Value: 7.0E-6
Constant
 
   kphosNFkB
Value: 0.001
Constant
 
   kphosp38
Value: 1.0E-7
Constant
 
   kphosp38ROS
Value: 1.0E-4
Constant
 
   kphosSmad1
Value: 2.0E-5
Constant
 
   kphosSmad2
Value: 4.0E-5
Constant
 
   kprodAGE
Value: 1.0E-6
Constant
 
   krelAlk1Alk5
Value: 0.01
Constant
 
   krelBaxBcl2
Value: 0.00167
Constant
 
   krelBaxBcl2Bec
Value: 0.00167
Constant
 
   krelBcl2Beclin
Value: 5.0E-4
Constant
 
   krelBecBaxBcl2
Value: 0.0167
Constant
 
   krelSmad1Smad4
Value: 0.0167
Constant
 
   krelSmad2Smad4
Value: 0.0167
Constant
 
   krelSmad7Alk1
Value: 0.001
Constant
 
   krelSmad7Alk5
Value: 1.0E-6
Constant
 
   krelTgfbAlk1
Value: 1.0E-6
Constant
 
   krelTgfbAlk5
Value: 1.0E-6
Constant
 
   kremROS
Value: 3.83E-4
Constant
 
   kremROSbySOD
Value: 1.0E-4
Constant
 
   ksynAcanmRNA
Constant
 
   ksynAcanmRNASox9A
Value: 4.6E-6
Constant
 
   ksynADAMTS5
Value: 5.0E-4
Constant
 
   ksynAggrecan
Value: 1.0E-6
Constant
 
   ksynAlk1
Value: 5.0E-6
Constant
 
   ksynAlk5
Value: 5.0E-6
Constant
 
   ksynBcl2
Value: 0.002
Constant
 
   ksynCol2
Value: 1.0E-7
Constant
 
   ksynCol2mRNA
Constant
 
   ksynCol2mRNASmad
Value: 1.0E-6
Constant
 
   ksynCol2mRNASox9A
Value: 1.0E-6
Constant
 
   ksynIkB
Value: 0.001
Constant
 
   ksynIL1
Value: 0.005
Constant
 
   ksynMMP13
Value: 3.2E-5
Constant
 
   ksynMMP13Runx2
Value: 1.5E-6
Constant
 
   ksynMMP2
Value: 5.0E-6
Constant
 
   ksynNatP
Constant
 
   ksynRAGE
Value: 1.0E-4
Constant
 
   ksynSmad7
Value: 1.0E-5
Constant
 
   ksynSOD
Value: 0.002
Constant
 
   ksynSox9
Value: 4.8E-4
Constant
 
   ksynSox9mRNA
Value: 1.0E-5
Constant
 
   ksynSox9mRNASox9A
Value: 5.0E-6
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000560

Curator's comment: (updated: 05 Dec 2014 17:00:19 GMT)

Figure 5C of the reference publication has been reproduced. One stochastic simulation was carried out using Copasi v4.14 (Build 89). In the paper, 500 stochastic simulations has been carried out and figure 5c is a randomly chosen simulation result.

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