An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation.
Khurana, Sakshi; Schivo, Stefano; Plass, Jacqueline R Met al.
2021 • In Frontiers in Bioengineering and Biotechnology, 9, p. 732917
BMP7; IGF; PTHrP; chondrogenesis; computational model; hypertrophy; signal transduction
Abstract :
[en] A fundamental question in cartilage biology is: what determines the switch between permanent cartilage found in the articular joints and transient hypertrophic cartilage that functions as a template for bone? This switch is observed both in a subset of OA patients that develop osteophytes, as well as in cell-based tissue engineering strategies for joint repair. A thorough understanding of the mechanisms regulating cell fate provides opportunities for treatment of cartilage disease and tissue engineering strategies. The objective of this study was to understand the mechanisms that regulate the switch between permanent and transient cartilage using a computational model of chondrocytes, ECHO. To investigate large signaling networks that regulate cell fate decisions, we developed the software tool ANIMO, Analysis of Networks with interactive Modeling. In ANIMO, we generated an activity network integrating 7 signal transduction pathways resulting in a network containing over 50 proteins with 200 interactions. We called this model ECHO, for executable chondrocyte. Previously, we showed that ECHO could be used to characterize mechanisms of cell fate decisions. ECHO was first developed based on a Boolean model of growth plate. Here, we show how the growth plate Boolean model was translated to ANIMO and how we adapted the topology and parameters to generate an articular cartilage model. In ANIMO, many combinations of overactivation/knockout were tested that result in a switch between permanent cartilage (SOX9+) and transient, hypertrophic cartilage (RUNX2+). We used model checking to prioritize combination treatments for wet-lab validation. Three combinatorial treatments were chosen and tested on metatarsals from 1-day old rat pups that were treated for 6 days. We found that a combination of IGF1 with inhibition of ERK1/2 had a positive effect on cartilage formation and growth, whereas activation of DLX5 combined with inhibition of PKA had a negative effect on cartilage formation and growth and resulted in increased cartilage hypertrophy. We show that our model describes cartilage formation, and that model checking can aid in choosing and prioritizing combinatorial treatments that interfere with normal cartilage development. Here we show that combinatorial treatments induce changes in the zonal distribution of cartilage, indication possible switches in cell fate. This indicates that simulations in ECHO aid in describing pathologies in which switches between cell fates are observed, such as OA.
Disciplines :
Engineering, computing & technology: Multidisciplinary, general & others
Author, co-author :
Khurana, Sakshi; Technical Medicine Centre, Department of Developmental BioEngineering, University
Schivo, Stefano ; Université de Liège - ULiège > Département d'aérospatiale et mécanique > Génie biomécanique ; Technical Medicine Centre, Department of Developmental BioEngineering, University ; Department of Formal Methods and Tools, CTIT Institute, University of Twente,
Plass, Jacqueline R M; Technical Medicine Centre, Department of Developmental BioEngineering, University
Mersinis, Nikolas; Technical Medicine Centre, Department of Developmental BioEngineering, University
Scholma, Jetse; Technical Medicine Centre, Department of Developmental BioEngineering, University
Kerkhofs, Johan ; Université de Liège - ULiège > Département d'aérospatiale et mécanique > Génie biomécanique
Zhong, Leilei; Technical Medicine Centre, Department of Developmental BioEngineering, University
van de Pol, Jaco; Department of Formal Methods and Tools, CTIT Institute, University of Twente, ; Dept. of Computer Science, Aarhus University, Aarhus, Denmark.
Langerak, Rom; Department of Formal Methods and Tools, CTIT Institute, University of Twente,
Geris, Liesbet ; Université de Liège - ULiège > GIGA > GIGA In silico medecine - Biomechanics Research Unit ; Biomechanics Section, Department of Mechanical Engineering, KU Leuven, Leuven,
Karperien, Marcel; Technical Medicine Centre, Department of Developmental BioEngineering, University
Post, Janine N; Technical Medicine Centre, Department of Developmental BioEngineering, University
Language :
English
Title :
An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation.
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