Article
Dynamic mathematical model of OA progression
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Published: | October 23, 2017 |
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Objectives: Currently there is a lack of translation of typically univariate preclinical findings into effective therapies in osteoarthritis (OA). OA-associated factors form usually only parts of a complex regulatory network driving the progression of OA and there is a limiting understanding of how different OA-associated factors are dynamically interrelated. Mathematical modelling is becoming a standard tool to summarise and integrate the dynamical interplay of causal factors/hypothesis in disease progression. Our aim is to develop a mathematical model of the multifactorial processes involved in OA progression with the help of a standardised preclinical mouse model. The goal is to improve the understanding of dynamics of OA progression.
Methods: OA was surgically induced in C57Bl/6 mice by transection of the medial collateral ligament and the medial meniscus (MCL-MM). In sham mice, skin and underlying tissue were cut to visualise the medial collateral ligament without transection. Mice were sacrificed at different time points between 2 and 8 weeks post injury and OA progression was analysed. Using computer vision and automated segmentation we produced time resolved quantitative immunohistochemistry to establish and parametrise our mathematical model.
Results and Conclusion: Surgical destabilisation of the knee joint induced progressive degeneration of cartilage with first structural changes becoming visible as early as 2 week post injury. We observe that the cartilage height in OA mice decreases at 8µm per week and 3µm per week for sham mice. We observe a linear trend in cartilage degradation. On the contrary, we observe two drops in chondrocyte populations, one early until week 2 (a 20% decrease), then a later drop after week 6 (a 20% further decrease).
Using our mathematical model, two phases of OA progression become visible. We suggest that the first drop in chondrocytes decreases extra cellular matrix synthesis, creating an imbalance, which initiates cartilage erosion. The progressive degradation presumably leads to altered biomechanics which in return induces further reduction in chondrocytes. In principle, if we observe similar progression in a variant of OA in humans, our mathematical model, with extensions, could be used to stratify patients in terms of their OA stage, guiding clinical intervention (Figure 1 [Fig. 1]).