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Cartilage endoplasmic reticulum stress may influence the onset but not the progression of experimental osteoarthritis

Lookup NU author(s): Dr Jamie Soul, Professor Michael BriggsORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 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.

Publication metadata

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

Year: 2019

Volume: 21

Issue: 1

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.

URL: https://doi.org/10.1186/s13075-019-1988-6

DOI: 10.1186/s13075-019-1988-6

PubMed id: 31511053

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