[en] Computational modeling can be used to investigate complex signaling networks in biology. However, most modeling tools are not suitable for molecular cell biologists with little background in mathematics. We have built a visual-based modeling tool for the investigation of dynamic networks. Here, we describe the development of computational models of cartilage development and osteoarthritis, in which a panel of relevant signaling pathways are integrated. In silico experiments give insight in the role of each of the pathway components and reveal which perturbations may deregulate the basal healthy state of cells and tissues. We used a previously developed computational modeling tool Analysis of Networks with Interactive Modeling (ANIMO) to generate an activity network integrating 7 signal transduction pathways resulting in a network containing over 50 nodes and 200 interactions. We performed in silico experiments to characterize molecular mechanisms of cell fate decisions. The model was used to mimic biological scenarios during cell differentiation using RNA-sequencing data of a variety of stem cell sources as input. In a case-study, we wet-lab-tested the model-derived hypothesis that expression of DKK1 (Dickkopf-1) and FRZB (Frizzled related protein, WNT antagonists) and GREM1 (gremlin 1, BMP antagonist) prevents IL1β (Interleukin 1 beta)-induced MMP (matrix metalloproteinase) expression, thereby preventing cartilage degeneration, at least in the short term. We found that a combination of DKK1, FRZB and GREM1 may play a role in modulating the effects of IL1β induced inflammation in human primary chondrocytes.
Disciplines :
Engineering, computing & technology: Multidisciplinary, general & others
Author, co-author :
Schivo, Stefano ; Université de Liège - ULiège > Département d'aérospatiale et mécanique > Génie biomécanique ; Department of Developmental BioEngineering, Technical Medicine Centre, University
Khurana, Sakshi; Department of Developmental BioEngineering, Technical Medicine Centre, University
Govindaraj, Kannan; Department of Developmental BioEngineering, Technical Medicine Centre, University
Scholma, Jetse; Department of Developmental BioEngineering, Technical Medicine Centre, University
Kerkhofs, Johan ; Université de Liège - ULiège > Département d'aérospatiale et mécanique > Génie biomécanique ; Prometheus, the Leuven R&D division of skeletal tissue engineering, KU Leuven,
Zhong, Leilei; Department of Developmental BioEngineering, Technical Medicine Centre, University
Huang, Xiaobin; Department of Developmental BioEngineering, Technical Medicine Centre, University
van de Pol, Jaco; Department of Formal Methods and Tools, CTIT institute, University of Twente,
Langerak, Rom; Department of Formal Methods and Tools, CTIT institute, University of Twente,
van Wijnen, André J; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
Geris, Liesbet ; Université de Liège - ULiège > GIGA > GIGA In silico medecine - Biomechanics Research Unit ; Prometheus, the Leuven R&D division of skeletal tissue engineering, KU Leuven,
Karperien, Marcel; Department of Developmental BioEngineering, Technical Medicine Centre, University
Post, Janine N; Department of Developmental BioEngineering, Technical Medicine Centre, University
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