2016 Conference on Computational Modelling with COPASI
Manchester Institute of Biotechnology, 12th – 13th May, 2016
1 - MRC/Arthritis Research UK Centre for Musculoskeletal Ageing (CIMA), Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, UK
Keywords: ageing, musculoskeletal, osteoarthritis, bone homeostasis, cartilage, stochastic simulation, oxidised proteins
Age-related musculoskeletal diseases such as osteoarthritis, osteoporosis and sarcopenia are a major cause of morbidity in the elderly population. The MRC/Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA) is a collaboration between the universities of Liverpool, Newcastle and Sheffield which was set up to develop an integrated approach to understand the mechanisms of ageing that affect musculoskeletal tissues. Since the molecular mechanisms involved are complex, we are using computational modelling to complement experimental work.
I will give an overview of the modelling work that is recently being carried out within CIMA and will then focus on three models, two which have been developed to investigate the mechanisms involved in osteoarthritis, and a third model of the molecular pathways involved in maintaining bone homeostasis. These models were constructed in a modular way using the Systems Biology Markup Language. Both deterministic and stochastic approaches were used and simulations and model analysis were carried out in COPASI.
The models were developed in collaboration with experimental scientists and a range of data were used to calibrate and validate the models. For example, histochemical and immunohistochemical data of cartilage showed many age-related changes including a decline in autophagy, an increase in apoptosis, and an increase in levels of oxidised proteins, matrix metalloproteinase-13 (MMP-13) level (an enzyme that is responsible for the pathological degradation of cartilage, a key feature of osteoarthritis). Since there was considerable cell-cell variability in the measured outcomes, we mainly used stochastic simulation to model age-related changes in cartilage. This model showed that the main source of this cellular heterogeneity is due to the stochastic nature of cellular damage, as most variability in the model output was seen in the levels of oxidized proteins. There was also considerable variability in the time at which damage starts to accrue, and this accounted for the observed wide variability in the activation of matrix degrading enzymes.