Hypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes

Abstract Cartilage tissue is avascular and hypoxic which regulates chondrocyte phenotype via stabilization of HIFs. Here, we investigated the role of hypoxia and HIFs in regulation of Rho and canonical Wnt signaling in chondrocytes. Our data demonstrates that hypoxia controls the expression of RhoA...

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Autores principales:	Ece Öztürk, Stefanie Hobiger, Evelin Despot-Slade, Michael Pichler, Marcy Zenobi-Wong
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/71246e7466b540d6b3b8e6c716d9cfd4
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spelling	oai:doaj.org-article:71246e7466b540d6b3b8e6c716d9cfd42021-12-02T12:30:16ZHypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes10.1038/s41598-017-09505-62045-2322https://doaj.org/article/71246e7466b540d6b3b8e6c716d9cfd42017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09505-6https://doaj.org/toc/2045-2322Abstract Cartilage tissue is avascular and hypoxic which regulates chondrocyte phenotype via stabilization of HIFs. Here, we investigated the role of hypoxia and HIFs in regulation of Rho and canonical Wnt signaling in chondrocytes. Our data demonstrates that hypoxia controls the expression of RhoA in chondrocytes in a context-dependent manner on the culturing conditions. Within a 3D microenvironment, hypoxia suppresses RhoA on which hypoxia-driven expression of chondrogenic markers depends. Conversely, hypoxia leads to upregulation of RhoA in chondrocytes on 2D with a failure in re-expression of chondrogenic markers. Similarly to RhoA, hypoxic regulation of Wnt/β-catenin signaling depends on the microenvironment. Hypoxia downregulates β-catenin within 3D hydrogels whereas it causes a potent increase on 2D. Hypoxia-induced suppression of canonical Wnt signaling in 3D contributes to the promotion of chondrogenic phenotype as induction of Wnt signaling abrogates the hypoxic re-differentiation of chondrocytes. Inhibiting Wnt/β-catenin signaling via stabilization of Axin2 leads to a synergistic enhancement of hypoxia-induced expression of chondrogenic markers. The effects of hypoxia on Rho and Wnt/β-catenin signaling are HIF-dependent as stabilizing HIFs under normoxia revealed similar effects on chondrocytes. The study reveals important insights on hypoxic signaling of chondrocytes and how hypoxia regulates cellular mechanisms depending on the cellular microenvironment.Ece ÖztürkStefanie HobigerEvelin Despot-SladeMichael PichlerMarcy Zenobi-WongNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ece Öztürk Stefanie Hobiger Evelin Despot-Slade Michael Pichler Marcy Zenobi-Wong Hypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes
description	Abstract Cartilage tissue is avascular and hypoxic which regulates chondrocyte phenotype via stabilization of HIFs. Here, we investigated the role of hypoxia and HIFs in regulation of Rho and canonical Wnt signaling in chondrocytes. Our data demonstrates that hypoxia controls the expression of RhoA in chondrocytes in a context-dependent manner on the culturing conditions. Within a 3D microenvironment, hypoxia suppresses RhoA on which hypoxia-driven expression of chondrogenic markers depends. Conversely, hypoxia leads to upregulation of RhoA in chondrocytes on 2D with a failure in re-expression of chondrogenic markers. Similarly to RhoA, hypoxic regulation of Wnt/β-catenin signaling depends on the microenvironment. Hypoxia downregulates β-catenin within 3D hydrogels whereas it causes a potent increase on 2D. Hypoxia-induced suppression of canonical Wnt signaling in 3D contributes to the promotion of chondrogenic phenotype as induction of Wnt signaling abrogates the hypoxic re-differentiation of chondrocytes. Inhibiting Wnt/β-catenin signaling via stabilization of Axin2 leads to a synergistic enhancement of hypoxia-induced expression of chondrogenic markers. The effects of hypoxia on Rho and Wnt/β-catenin signaling are HIF-dependent as stabilizing HIFs under normoxia revealed similar effects on chondrocytes. The study reveals important insights on hypoxic signaling of chondrocytes and how hypoxia regulates cellular mechanisms depending on the cellular microenvironment.
format	article
author	Ece Öztürk Stefanie Hobiger Evelin Despot-Slade Michael Pichler Marcy Zenobi-Wong
author_facet	Ece Öztürk Stefanie Hobiger Evelin Despot-Slade Michael Pichler Marcy Zenobi-Wong
author_sort	Ece Öztürk
title	Hypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes
title_short	Hypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes
title_full	Hypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes
title_fullStr	Hypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes
title_full_unstemmed	Hypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes
title_sort	hypoxia regulates rhoa and wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/71246e7466b540d6b3b8e6c716d9cfd4
work_keys_str_mv	AT eceozturk hypoxiaregulatesrhoaandwntbcateninsignalinginacontextdependentwaytocontrolredifferentiationofchondrocytes AT stefaniehobiger hypoxiaregulatesrhoaandwntbcateninsignalinginacontextdependentwaytocontrolredifferentiationofchondrocytes AT evelindespotslade hypoxiaregulatesrhoaandwntbcateninsignalinginacontextdependentwaytocontrolredifferentiationofchondrocytes AT michaelpichler hypoxiaregulatesrhoaandwntbcateninsignalinginacontextdependentwaytocontrolredifferentiationofchondrocytes AT marcyzenobiwong hypoxiaregulatesrhoaandwntbcateninsignalinginacontextdependentwaytocontrolredifferentiationofchondrocytes
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Hypoxia regulates RhoA and Wnt/β-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes

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