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

Abstract

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 (+/+), ColIITgcog (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.

Endoplasmic Reticulum Stress Regulates Scleral Remodeling in a Guinea Pig Model of Form-Deprivation Myopia

“…But prolonged ER stress ultimately contributed to decrease of collagen and myopia development. However, this effect of ER stress on onset and progression of FDM need to be further verified in animal models by genetic predisposition or preconditioning intervention [46]. In general, we demonstrated the characteristic of ER stress response in vitro, which established the foundation for the further study.…”

Tetramethylpyrazine alleviates endoplasmic reticulum stress‑activated apoptosis and related inflammation in chondrocytes

“…Typically, susceptibility to ER stress in the ColIITgcog mouse model has a beneficial effect. Specifically, it can mitigate OA due to the effective management of ER stress within articular chondrocytes ( 30 ).…”

New developments in chondrocyte ER-stress and related diseases

“…ATF6α does not contribute to the capacity of the unfolded protein response in the context of osteoarthritis Strikingly, although several studies suggested that ATF6 signalling may be responsible for the regulation of Xbp1 during OA progression, no difference in OA onset or progression could be seen in ATF6α-deficient mice after DMM surgery, suggesting that ATF6α may not be as relevant in this context as other branches of the UPR 50 . Previous studies have shown a differential expression of ATF6α and ATF6β in a cartilage growth plate and a differentiation state-dependent modulation of ATF6 signalling 16 .…”

“…An adapted endoplasmic reticulum stress response could delay the onset of osteoarthritis A recent study by Kung et al employed the dislocation of the medial meniscus (DMM) mouse model to study trauma-induced OA 50 . Interestingly, BiP expression was markedly increased after DMM surgery in wild-type mice, clearly demonstrating an involvement of ER stress and the UPR in the pathogenesis of OA.…”