An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation

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 a...

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Autores principales:	Sakshi Khurana, Stefano Schivo, Jacqueline R. M. Plass, Nikolas Mersinis, Jetse Scholma, Johan Kerkhofs, Leilei Zhong, Jaco van de Pol, Rom Langerak, Liesbet Geris, Marcel Karperien, Janine N. Post
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	computational model signal transduction IGF BMP7 PTHrP chondrogenesis Biotechnology TP248.13-248.65
Acceso en línea:	https://doaj.org/article/7987b8cda5b64370984e24d6236274bd
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spelling	oai:doaj.org-article:7987b8cda5b64370984e24d6236274bd2021-11-15T16:17:12ZAn ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation2296-418510.3389/fbioe.2021.732917https://doaj.org/article/7987b8cda5b64370984e24d6236274bd2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fbioe.2021.732917/fullhttps://doaj.org/toc/2296-4185A 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.Sakshi KhuranaStefano SchivoStefano SchivoJacqueline R. M. PlassNikolas MersinisJetse ScholmaJohan KerkhofsLeilei ZhongJaco van de PolJaco van de PolRom LangerakLiesbet GerisMarcel KarperienJanine N. PostFrontiers Media S.A.articlecomputational modelsignal transductionIGFBMP7PTHrPchondrogenesisBiotechnologyTP248.13-248.65ENFrontiers in Bioengineering and Biotechnology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	computational model signal transduction IGF BMP7 PTHrP chondrogenesis Biotechnology TP248.13-248.65
spellingShingle	computational model signal transduction IGF BMP7 PTHrP chondrogenesis Biotechnology TP248.13-248.65 Sakshi Khurana Stefano Schivo Stefano Schivo Jacqueline R. M. Plass Nikolas Mersinis Jetse Scholma Johan Kerkhofs Leilei Zhong Jaco van de Pol Jaco van de Pol Rom Langerak Liesbet Geris Marcel Karperien Janine N. Post An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation
description	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.
format	article
author	Sakshi Khurana Stefano Schivo Stefano Schivo Jacqueline R. M. Plass Nikolas Mersinis Jetse Scholma Johan Kerkhofs Leilei Zhong Jaco van de Pol Jaco van de Pol Rom Langerak Liesbet Geris Marcel Karperien Janine N. Post
author_facet	Sakshi Khurana Stefano Schivo Stefano Schivo Jacqueline R. M. Plass Nikolas Mersinis Jetse Scholma Johan Kerkhofs Leilei Zhong Jaco van de Pol Jaco van de Pol Rom Langerak Liesbet Geris Marcel Karperien Janine N. Post
author_sort	Sakshi Khurana
title	An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation
title_short	An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation
title_full	An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation
title_fullStr	An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation
title_full_unstemmed	An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation
title_sort	echo of cartilage: in silico prediction of combinatorial treatments to switch between transient and permanent cartilage phenotypes with ex vivo validation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/7987b8cda5b64370984e24d6236274bd
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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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