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

S.J.B Snelling,R.K Davidson,T.E Swingler,L.T.T Le,M.J Barter,K.L Culley,A Price,A.J Carr,I.M Clark

doi:10.1016/j.joca.2015.11.021

Abstract

SummaryObjectiveDickkopf-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.MethodsDkk3 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-1β (IL1β) and oncostatin-M (OSM). Dkk3 gene expression was measured in cartilage following murine hip avulsion. Whether Dkk3 influenced Wnt, TGFβ and activin cell signaling was assessed in primary human chondrocytes and SW1353 chondrosarcoma cells using qRT-PCR and luminescence assays.ResultsIncreased 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 IL1β 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. TGFβ signaling was enhanced by Dkk3 whilst Wnt3a and activin signaling were inhibited.ConclusionsWe 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.

Highlights

Osteoarthritis (OA) is characterized by loss of articular cartilage, joint pain and instability
Dysregulation of cell signaling pathways likely contributes to OA pathogenesis by reducing the chondrocyte's ability to maintain cartilage integrity, leading to or exacerbating the phenotypic shift associated with OA
Primary human OA cartilage and synovium were obtained from age-matched individuals undergoing hip replacement for OA and control cartilage and synovium obtained upon hip replacement for neck-of-femur fracture (NOF); cartilage OA n 1⁄4 13, NOF n 1⁄4 12, OA synovium n 1⁄4 8; NOF synovium n 1⁄4 11

Summary

Introduction

Osteoarthritis (OA) is characterized by loss of articular cartilage, joint pain and instability. Dysregulation of cell signaling pathways likely contributes to OA pathogenesis by reducing the chondrocyte's ability to maintain cartilage integrity, leading to or exacerbating the phenotypic shift associated with OA. S.J.B. Snelling et al / Osteoarthritis and Cartilage 24 (2016) 883e891 that inhibits proliferation of cancer cells and is downregulated in several types of human cancer8e10. Snelling et al / Osteoarthritis and Cartilage 24 (2016) 883e891 that inhibits proliferation of cancer cells and is downregulated in several types of human cancer8e10 It can modulate inflammatory cell activity, maintain tissue organisation via TGFb signaling and can protect against myocardial infarction-induced fibrosis11e14. Our aim was to assess whether Dkk[3] shows aberrant expression in human OA and to establish whether it can regulate chondrocyte behaviour and OA-associated cartilage degradation in vitro

Methods

Results

Conclusion