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

• Published in: Arthritis research & therapy Vol. 21; no. 1; pp. 206 - 13
• Main Authors: Kung, Louise H W, Mullan, Lorna, Soul, Jamie, Wang, Ping, Mori, Kazutoshi, Bateman, John F, Briggs, Michael D, Boot-Handford, Raymond P
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.09.2019; BioMed Central; BMC
• Subjects: Animal genetic engineering; Animals; Apoptosis; Arthritis; ATF6α; Biomarkers - metabolism; Cartilage, Articular; Collagen; Control; Development and progression; Disease Models, Animal; Disease Progression; EDTA; Endoplasmic reticulum; Endoplasmic reticulum (ER) stress; Endoplasmic Reticulum Stress - physiology; Gene Expression Regulation; Histology; Immunohistochemistry; Male; Medial meniscus destabilisation (DMM); Mice; Mouse; Osteoarthritis; Osteoarthritis - genetics; Osteoarthritis - metabolism; Osteoarthritis - pathology; Risk factors; RNA; RNA - genetics; RNA sequencing; Rodents; Stress (Physiology); Medial meniscus destabilisation (DMM); Endoplasmic reticulum (ER) stress; Mouse; RNA-seq; ATF6α; Histology; Osteoarthritis; Apoptosis
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-019-1988-6

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. OA was induced in male wild-type (+/+), ColIITg (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 Tg . 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. 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. 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.