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A homeostatic function of CXCR2 signalling in articular cartilage

Sherwood, J, Bertrand, J, Nalesso, G, Poulet, B, Pitsillides, A, Brandolini, L, Karystinou, A, De Bari, C, Luyten, FP, Pitzalis, C , Pap, T and Dell'Accio, F (2014) A homeostatic function of CXCR2 signalling in articular cartilage Annals of the Rheumatic Diseases, 74 (12). pp. 2207-2215.

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Abstract

Objective ELR+ CXC chemokines are heparin-binding cytokines signalling through the CXCR1 and CXCR2 receptors. ELR+ CXC chemokines have been associated with inflammatory arthritis due to their capacity to attract inflammatory cells. Here, we describe an unsuspected physiological function of these molecules in articular cartilage homeostasis. Methods Chemokine receptors and ligands were detected by immunohistochemistry, western blotting and RT-PCR. Osteoarthritis was induced in wild-type and CXCR2−/− mice by destabilisation of the medial meniscus (DMM). CXCR1/2 signalling was inhibited in vitro using blocking antibodies or siRNA. Chondrocyte phenotype was analysed using Alcian blue staining, RT-PCR and western blotting. AKT phosphorylation and SOX9 expression were upregulated using constitutively active AKT or SOX9 plasmids. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. Results CXCL6 was expressed in healthy cartilage and was retained through binding to heparan sulfate proteoglycans. CXCR2−/− mice developed more severe osteoarthritis than wild types following DMM, with increased chondrocyte apoptosis. Disruption of CXCR1/2 in human and CXCR2 signalling in mouse chondrocytes led to a decrease in extracellular matrix production, reduced expression of chondrocyte differentiation markers and increased chondrocyte apoptosis. CXCR2-dependent chondrocyte homeostasis was mediated by AKT signalling since forced expression of constitutively active AKT rescued the expression of phenotypic markers and the apoptosis induced by CXCR2 blockade. Conclusions Our study demonstrates an important physiological role for CXCR1/2 signalling in maintaining cartilage homeostasis and suggests that the loss of ELR+ CXC chemokines during cartilage breakdown in osteoarthritis contributes to the characteristic loss of chondrocyte phenotypic stability.

Item Type: Article
Subjects : Veterinary Medicine
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
NameEmailORCID
Sherwood, JUNSPECIFIEDUNSPECIFIED
Bertrand, JUNSPECIFIEDUNSPECIFIED
Nalesso, GUNSPECIFIEDUNSPECIFIED
Poulet, BUNSPECIFIEDUNSPECIFIED
Pitsillides, AUNSPECIFIEDUNSPECIFIED
Brandolini, LUNSPECIFIEDUNSPECIFIED
Karystinou, AUNSPECIFIEDUNSPECIFIED
De Bari, CUNSPECIFIEDUNSPECIFIED
Luyten, FPUNSPECIFIEDUNSPECIFIED
Pitzalis, CUNSPECIFIEDUNSPECIFIED
Pap, TUNSPECIFIEDUNSPECIFIED
Dell'Accio, FUNSPECIFIEDUNSPECIFIED
Date : 18 August 2014
Identification Number : 10.1136/annrheumdis-2014-205546
Copyright Disclaimer : Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/
Depositing User : Symplectic Elements
Date Deposited : 07 Apr 2017 10:14
Last Modified : 07 Apr 2017 10:14
URI: http://epubs.surrey.ac.uk/id/eprint/813982

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