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Lookup NU author(s): Dr Jamie Soul,
Professor Michael Briggs
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2019 The Author(s).Background: Osteoarthritis has been associated with a plethora of pathological factors and one which has recently emerged is chondrocyte endoplasmic reticulum (ER) stress. ER stress is sensed by key ER-resident stress sensors, one of which is activating transcription factor 6 (ATF6). The purpose of this study is to determine whether increased ER stress plays a role in OA. Methods: OA was induced in male wild-type (+/+), ColIITg cog (c/c) and Atf6α -/- mice by destabilisation of the medial meniscus (DMM). c/c mice have increased ER stress in chondrocytes via the collagen II promoter-driven expression of ER stress-inducing Tgcog. Knee joints were scored histologically for OA severity. RNA-seq was performed on laser-micro-dissected RNA from cartilage of +/+ and c/c DMM-operated mice. Results: In situ hybridisation demonstrated a correlation between the upregulation of ER stress marker, BiP, and early signs of proteoglycan loss and cartilage damage in DMM-operated +/+ mice. Histological analysis revealed a significant reduction in OA severity in c/c mice compared with +/+ at 2 weeks post-DMM. This chondroprotective effect in c/c mice was associated with a higher ambient level of BiP protein prior to DMM and a delay in chondrocyte apoptosis. RNA-seq analysis suggested Xbp1-regulated networks to be significantly enriched in c/c mice at 2 weeks post-DMM. Compromising the ER through genetically ablating Atf6α, a key ER stress sensor, had no effect on DMM-induced OA severity. Conclusion: Our studies indicate that an increased capacity to effectively manage increases in ER stress in articular cartilage due either to pre-conditioning as a result of prior exposure to ER stress or to genetic pre-disposition may be beneficial in delaying the onset of OA, but once established, ER stress plays no significant role in disease progression.
Author(s): Kung LHW, Mullan L, Soul J, Wang P, Mori K, Bateman JF, Briggs MD, Boot-Handford RP
Publication type: Article
Publication status: Published
Journal: Arthritis Research and Therapy
Online publication date: 11/09/2019
Acceptance date: 28/08/2019
Date deposited: 02/10/2019
ISSN (print): 1478-6354
ISSN (electronic): 1478-6362
Publisher: BioMed Central Ltd.
PubMed id: 31511053
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