ECHO, the executable CHOndrocyte: A computational model to study articular chondrocytes in health and disease.
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.
['Schivo|Stefano|S|', 'Khurana|Sakshi|S|', 'Govindaraj|Kannan|K|', 'Scholma|Jetse|J|', 'Kerkhofs|Johan|J|', 'Zhong|Leilei|L|', 'Huang|Xiaobin|X|', 'van de Pol|Jaco|J|', 'Langerak|Rom|R|', 'van Wijnen|André J|AJ|', 'Geris|Liesbet|L|', 'Karperien|Marcel|M|', 'Post|Janine N|JN|']
D000818:Animals D002358:Cartilage, Articular D019070:Cell Lineage D019902:Chondrocytes D003198:Computer Simulation D050659:Core Binding Factor Alpha 1 Subunit D004194:Disease D016326:Extracellular Matrix Proteins D005110:Extracellular Space D051157:Frizzled Receptors D006262:Health D006801:Humans D036341:Intercellular Signaling Peptides and Proteins D053583:Interleukin-1beta D008024:Ligands D010003:Osteoarthritis D055758:SOX9 Transcription Factor
ECHO Chondrocyte Computational model Cartilage Osteoarthritis ANIMO Hypertrophy Interleukin-1beta RUNX2 SOX9