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

Louise Kung, Lorna Mullan, Jamie Soul, Ping Wang, Kazutoshi Mori, John F. Bateman, Michael D. Briggs, Ray Boot-Handford

Research output: Contribution to journalArticlepeer-review


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 up-regulation 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.
Original languageEnglish
JournalArthritis Research & Therapy
Publication statusPublished - 11 Sept 2019


  • Endoplasmic reticulum (ER) stress
  • osteoarthritis
  • mouse
  • medial meniscus destabilisation (DMM)
  • ATF6α
  • apoptosis
  • histology
  • RNAseq


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