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WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways

Nalesso, G, Sherwood, J, Bertrand, J, Pap, T, Ramachandran, M, De Bari,, C, Pitzalis, C and Dell’Accio, F (2011) WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways Journal of Cell Biology, 193 (3). pp. 551-564.

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Abstract

Activation and disruption of Wnt/β-catenin signaling both result in cartilage breakdown via unknown mechanisms. Here we show that both WNT-3A and the Wnt inhibitor DKK1 induced de-differentiation of human articular chondrocytes through simultaneous activation of β-catenin–dependent and independent responses. WNT-3A activates both the β-catenin–dependent canonical pathway and the Ca2+/CaMKII noncanonical pathways, with distinct transcriptional targets. WNT-3A promotes cell proliferation and loss of expression of the chondrocyte markers COL2A1, Aggrecan, and SOX9; however, proliferation and AXIN2 up-regulation are downstream of the canonical pathway and are rescued by DKK1, whereas the loss of differentiation markers is CaMKII dependent. Finally, we showed that in chondrocytes, the Ca2+/CaMKII-dependent and β-catenin–dependent pathways are reciprocally inhibitory, thereby explaining why DKK1 can induce loss of differentiation through de-repression of the CaMKII pathway. We propose a novel model in which a single WNT can simultaneously activate different pathways with distinct and independent outcomes and with reciprocal regulation. This offers an opportunity for selective pharmacological targeting.

Item Type: Article
Subjects : Veterinary Medicine
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
AuthorsEmailORCID
Nalesso, GUNSPECIFIEDUNSPECIFIED
Sherwood, JUNSPECIFIEDUNSPECIFIED
Bertrand, JUNSPECIFIEDUNSPECIFIED
Pap, TUNSPECIFIEDUNSPECIFIED
Ramachandran, MUNSPECIFIEDUNSPECIFIED
De Bari,, CUNSPECIFIEDUNSPECIFIED
Pitzalis, CUNSPECIFIEDUNSPECIFIED
Dell’Accio, FUNSPECIFIEDUNSPECIFIED
Date : 2 May 2011
Identification Number : https://doi.org/10.1083/jcb.201011051
Copyright Disclaimer : © 2011 Nalesso et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
Depositing User : Symplectic Elements
Date Deposited : 07 Apr 2017 13:22
Last Modified : 07 Apr 2017 13:22
URI: http://epubs.surrey.ac.uk/id/eprint/813989

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