Article Text

Extended report
Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage
  1. Wang Hui1,
  2. David A Young1,
  3. Andrew D Rowan1,
  4. Xin Xu2,
  5. Tim E Cawston1,
  6. Carole J Proctor1,3
  1. 1MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
  2. 2Biomedicine Biobank, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
  3. 3Newcastle University Institute for Ageing, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
  1. Correspondence to Dr Carole Proctor, MRC/Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; carole.proctor{at}ncl.ac.uk

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.

  • Chondrocytes
  • Osteoarthritis
  • Synovial fluid

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