Crosstalk Modeling of Wnt, BMP and ERK Pathways during osteochondrogenic differentiation

The in vitro engineering of tissues may be achieved by mimicking in vivo tissue development. Although multiple skeletal tissue engineering applications already exist, the underlying mechanisms at protein level are often poorly understood. Growth factors and protein pathways precisely navigate mesenchymal stem cells trough the correct cascades. A detailed understanding of these cascades will enable us to develop efficient and robust production methods, which are required for large scale tissue engineering applications. Multiple studies hypothesize that the Wnt/β-catenin pathway acts as a switching mechanism to determine the differential fate of esenchymal cells in osteoblasts or chondrocytes during skeletogenesis. The concentration of β-catenin is a key factor in this mechanism. Wnt upregulates the productionof β-catenin which in turn upregulates Runx2 and downregulates Sox9. High concentrations of Runx2 relative to Sox9 lead to osteoblasts, while the opposite situation leads to chondrocytes. Crosstalks of the Wnt pathway with other pathways such as that of BMP and ERK expand the amount of factors that can influence β-catenin, turning the linear signaling cascade into a complex network with multiple starting conditions. A mathematical model was derived from literature describing the pathways of BMP, Wnt and ERK as well as various crosstalks between these pathways that were suggested in
literature. CellDesigner™ was used to formulate, solve and visualize the Ordinary Differential Equations describing the temporal evolution of the various model constituents. Multiple starting conditions (various concentrations of BMP, Wnt and ERK) were examined to clarify the crosstalk effect. Modeling various crosstalks proposed in literature resulted in a mutual inhibitory effect between Wnt and BMP signaling, an effect independently described in literature. Experiments are ongoing to corroborate the model predictions.