Hui2016 - Age-related changes in articular cartilage
This model is described in the article:
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.
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Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage.
- Hui W, Young DA, Rowan AD, Xu X, Cawston TE, Proctor CJ
- Annals of the rheumatic diseases , 2/ 2016 , Volume 75 , pages: 449-458 , PubMed ID: 25475114
- MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
- To use a computational approach to investigate the cellular and extracellular matrix changes that occur with age in the knee joints of mice.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.A progressive loss of cartilage matrix occurred with age. Nitrotyrosine, MMP-13 and activin receptor-like kinase-1 (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-β 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.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.
Metadata information
Gene Ontology age-dependent response to oxidative stress involved in replicative cell aging
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000560_url.xml | SBML L2V4 representation of Hui2014 - Age-related changes in articular cartilage | 174.88 KB | Preview | Download |
Additional files |
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| BIOMD0000000560.xpp | Auto-generated XPP file | 30.82 KB | Preview | Download |
| BIOMD0000000560.vcml | Auto-generated VCML file | 897.00 Bytes | Preview | Download |
| BIOMD0000000560.png | Auto-generated Reaction graph (PNG) | 3.91 MB | Preview | Download |
| BIOMD0000000560.svg | Auto-generated Reaction graph (SVG) | 413.02 KB | Preview | Download |
| BIOMD0000000560-biopax3.owl | Auto-generated BioPAX (Level 3) | 346.89 KB | Preview | Download |
| BIOMD0000000560.sci | Auto-generated Scilab file | 27.02 KB | Preview | Download |
| BIOMD0000000560-biopax2.owl | Auto-generated BioPAX (Level 2) | 196.80 KB | Preview | Download |
| BIOMD0000000560.pdf | Auto-generated PDF file | 755.17 KB | Preview | Download |
| BIOMD0000000560_urn.xml | Auto-generated SBML file with URNs | 172.78 KB | Preview | Download |
| BIOMD0000000560.m | Auto-generated Octave file | 42.27 KB | Preview | Download |
- Model originally submitted by : Carole Proctor
- Submitted: Feb 20, 2014 1:27:41 PM
- Last Modified: Sep 4, 2019 3:34:15 PM
Revisions
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Version: 4
- Submitted on: Sep 4, 2019 3:34:15 PM
- Submitted by: Krishna Kumar Tiwari
- With comment: Edited model metadata online.
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Version: 2
- Submitted on: Apr 8, 2016 6:51:50 PM
- Submitted by: Carole Proctor
- With comment: Current version of Hui2014 - Age-related changes in articular cartilage
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Version: 1
- Submitted on: Feb 20, 2014 1:27:41 PM
- Submitted by: Carole Proctor
- With comment: Original import of BIOMD0000000560.xml.origin
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revisions as only public revisions are displayed here. Any private revisions
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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| AcanmRNA Aggrecan core protein |
0.0 item |
| ADAMTS5 A disintegrin and metalloproteinase with thrombospondin motifs 5 |
0.0 item |
| Alk1 Serine/threonine-protein kinase receptor R3 |
500.0 item |
| Alk1 Alk5 Serine/threonine-protein kinase receptor R3 ; TGF-beta receptor type-1 |
0.0 item |
| Alk5 TGF-beta receptor type-1 |
500.0 item |
| Smad1 P Smad4 Mothers against decapentaplegic homolog 1 ; Mothers against decapentaplegic homolog 4 ; phosphoprotein |
0.0 item |
| Smad2 Mothers against decapentaplegic homolog 2 |
600.0 item |
| Smad2 P Mothers against decapentaplegic homolog 2 ; phosphoprotein |
0.0 item |
| Alk5 dimer TGF-beta receptor type-1 |
0.0 item |
| Reactions | Rate | Parameters |
|---|---|---|
| Sox9_A => Sox9_A + AcanmRNA; Sox9_A | ksynAcanmRNASox9A*Sox9_A | ksynAcanmRNASox9A = 4.6E-6 |
| AcanmRNA => Sink; AcanmRNA | kdegAcanmRNA*AcanmRNA | kdegAcanmRNA = 9.0E-6 |
| AcanmRNA => AcanmRNA + Aggrecan; AcanmRNA | ksynAggrecan*AcanmRNA | ksynAggrecan = 1.0E-6 |
| IL1 => IL1 + ADAMTS5; IL1 | ksynADAMTS5*IL1 | ksynADAMTS5 = 5.0E-4 |
| Alk1_Alk5 => Alk1 + Alk5; Alk1_Alk5 | krelAlk1Alk5*Alk1_Alk5 | krelAlk1Alk5 = 0.01 |
| Source => Alk1; Source | ksynAlk1*Source | ksynAlk1 = 5.0E-6 |
| Tgfb_A + Alk1_Alk5 => Tgfb_Alk1_Alk5; Tgfb_A, Alk1_Alk5 | kbinTgfbAlk1*Tgfb_A*Alk1_Alk5 | kbinTgfbAlk1 = 2.0E-5 |
| Tgfb_Alk1_Alk5 => Tgfb_A + Alk1_Alk5; Tgfb_Alk1_Alk5 | krelTgfbAlk1*Tgfb_Alk1_Alk5 | krelTgfbAlk1 = 1.0E-6 |
| Source => Alk5; Source | ksynAlk5*Source | ksynAlk5 = 5.0E-6 |
| Alk5 => Alk5_dimer; Alk5 | kdimerAlk5*Alk5*(Alk5-1)*0.5 | kdimerAlk5 = 2.0E-4 |
| Smad1_P_Smad4 => Smad1_P + Smad4; Smad1_P_Smad4 | krelSmad1Smad4*Smad1_P_Smad4 | krelSmad1Smad4 = 0.0167 |
| Smad2_P => Smad2; Smad2_P | kdephosSmad2*Smad2_P | kdephosSmad2 = 0.006 |
| Tgfb_Alk5_dimer + Smad2 => Tgfb_Alk5_dimer + Smad2_P; Tgfb_Alk5_dimer, Smad2 | kphosSmad2*Tgfb_Alk5_dimer*Smad2 | kphosSmad2 = 4.0E-5 |
| Alk5_dimer => Alk5; Alk5_dimer | kdedimerAlk5*Alk5_dimer | kdedimerAlk5 = 0.001 |
| Tgfb_A + Alk5_dimer => Tgfb_Alk5_dimer; Tgfb_A, Alk5_dimer | kbinTgfbAlk5*Tgfb_A*Alk5_dimer | kbinTgfbAlk5 = 3.0E-5 |
(added: 05 Dec 2014, 17:00:19, updated: 05 Dec 2014, 17:00:19)