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Dickkopf-3 is upregulated in osteoarthritis and has a chondroprotective role

Lookup NU author(s): Dr Matthew Barter

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Abstract

Objective: Dickkopf-3 (Dkk3) is a non-canonical member of the Dkk family of Wnt antagonists and its upregulation has been reported in microarray analysis of cartilage from mouse models of osteoarthritis (OA). In this study we assessed Dkk3 expression in human OA cartilage to ascertain its potential role in chondrocyte signaling and cartilage maintenance.Methods: Dkk3 expression was analysed in human adult OA cartilage and synovial tissues and during chondrogenesis of ATDC5 and human mesenchymal stem cells. The role of Dkk3 in cartilage maintenance was analysed by incubation of bovine and human cartilage explants with interleukin-1 beta (IL1 beta) and oncostatin-M (OSM). Dkk3 gene expression was measured in cartilage following murine hip avulsion. Whether Dkk3 influenced Wnt, TGF beta and activin cell signaling was assessed in primary human chondrocytes and SW1353 chondrosarcoma cells using qRT-PCR and luminescence assays.Results: Increased gene and protein levels of Dkk3 were detected in human OA cartilage, synovial tissue and synovial fluid. DKK3 gene expression was decreased during chondrogenesis of both ATDC5 cells and humans MSCs. Dkk3 inhibited IL1 beta and OSM-mediated proteoglycan loss from human and bovine cartilage explants and collagen loss from bovine cartilage explants. Cartilage DKK3 expression was decreased following hip avulsion injury. TGF beta signaling was enhanced by Dkk3 whilst Wnt3a and activin signaling were inhibited.Conclusions: We provide evidence that Dkk3 is upregulated in OA and may have a protective effect on cartilage integrity by preventing proteoglycan loss and helping to restore OA-relevant signaling pathway activity. Targeting Dkk3 may be a novel approach in the treatment of OA. (c) 2015 The Authors. Published by Elsevier Ltd and Osteoarthritis Research Society International.


Publication metadata

Author(s): Snelling SJB, Davidson RK, Swingler TE, Le LTT, Barter MJ, Culley KL, Price A, Carr AJ, Clark IM

Publication type: Article

Publication status: Published

Journal: Osteoarthritis and Cartilage

Year: 2016

Volume: 24

Issue: 5

Pages: 883-891

Print publication date: 01/05/2016

Online publication date: 12/12/2015

Acceptance date: 24/11/2015

ISSN (print): 1063-4584

ISSN (electronic): 1522-9653

Publisher: Elsevier Science Ltd.

URL: http://dx.doi.org/10.1016/j.joca.2015.11.021

DOI: 10.1016/j.joca.2015.11.021


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