title: Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage.
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 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.
  
  
  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.
authors.affiliation: MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Wang
authors.initials: W
authors.lastname: Hui
authors.affiliation: MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Young
authors.affiliation: MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rowan
authors.affiliation: Biomedicine Biobank, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Tim E
authors.initials: TE
authors.lastname: Cawston
authors.affiliation: MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK Newcastle University Institute for Ageing, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: Carole J
authors.initials: CJ
authors.lastname: Proctor
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D002358:Cartilage, Articular / Q000502:physiology*; D024043:Collagen Type II / Q000378:metabolism; D003198:Computer Simulation; D005109:Extracellular Matrix / Q000378:metabolism; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism; D007719:Knee Joint / Q000502:physiology*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D024043:Collagen Type II; D007375:Interleukin-1; D016212:Transforming Growth Factor beta; C002744:3-nitrotyrosine; D014443:Tyrosine; D030201:Activin Receptors, Type I; D053509:Matrix Metalloproteinase 13
keywords: Chondrocytes; Osteoarthritis; Synovial fluid