IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis

Abstract

IRE1 is an important central regulator of unfolded protein response (UPR) in the endoplasmic reticulum (ER) because of its ability to regulate cell fate as a function of stress sensing. When misfolded proteins accumulated in chondrocytes ER, IRE1 disintegrates with BIP/GRP78 and undergoes dimer/oligomerization and transautophosphorylation. These two processes are mediated through an enzyme activity of IRE1 to activate endoribonuclease and generates XBP1 by unconventional splicing of XBP1 messenger RNA. Thereby promoting the transcription of UPR target genes and apoptosis. The deficiency of inositol‐requiring enzyme 1α (IRE1α) in chondrocytes downregulates prosurvival factors XBP1S and Bcl‐2, which enhances the apoptosis of chondrocytes through increasing proapoptotic factors caspase‐3, p‐JNK, and CHOP. Meanwhile, the activation of IRE1α increases chondrocyte viability and reduces cell apoptosis. However, the understanding of IRE1 responses and cell death fate remains controversial. This review provides updated data about the role IRE1 plays in chondrocytes and new insights about the potential efficacy of IRE1 regulation in cartilage repair and osteoarthritis treatment.

Salicin modifies osteoarthritis progression by binding on IRE1α and inhibiting IRE1α mediated endoplasmic reticulum stress

“…Worth mention, IRE1α plays key role in chondrocytes proliferation, ECM production etc. 32 , which indicates the regulatory function of IRE1α mediated ER stress in chondrocytes proliferation and degeneration. Jacqueline et al 33 found two top risk factors for OA, age and obesity, were highly associated with ER stress, and resveratrol could mitigate early joint degeneration by inhibiting ER stress.…”

“…Worth mention, IRE1α plays key role in chondrocytes proliferation, ECM production etc. 32 , which indicates the regulatory function of IRE1α mediated ER stress in chondrocytes proliferation and degeneration.…”

“…could cause excessive unfolding or misfolded proteins on ER and trigger ER stress 33,40 . Huang et al 32 reported that IRE1α regulates chondrocytes apoptosis by activating NF-κB signaling. Ye et al 47 reported phosphorylated IRE1α activating NF-κB signaling by releasing IκBα.…”

Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Ankylosing Spondylitis

“…When misfolded proteins accumulated in chondrocytes endoplasmic reticulum (ER), endoribonuclease was activated to generates XBP1 by unconventional splicing of XBP1 messenger RNA. Thereby promoting the transcription of UPR target genes and apoptosis [45] . Furthermore, XBP1 was essential for pro-in ammatory cytokine responses in macrophages and is dependent upon nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 [46] .…”

Role of Caspase Family in Intervertebral Disc Degeneration and Its Therapeutic Prospects

“…Under the action of RIDD, the degradation of anti-caspase-2 microRNAs triggers the activation of the apoptotic promoter caspase-2, which subsequently triggers an endogenous mitochondria-dependent apoptotic pathway [ 101 ]. Similarly, IRE1α can also activate the ASK1-JNK signaling pathway by recruiting TRAF2, triggering apoptosis through the mitochondrial pathway, which has been demonstrated in chondrocyte apoptosis [ 102 ]. When ER stress occurs, calcium homeostasis is disrupted, and a large number of calcium ions in the ER are released into the cytoplasm through RyR and IP3R protein channels.…”