Endoplasmic Reticulum Stress in the Progression from Lumbar Disc Degeneration to Herniation: Mechanisms and Progress in Intervention
ZHANG Ying1, XUE Xu2*, MEI Yongjie3, AN Chengqiang1, WU Yu1
LIDD (lumbar intervertebral disc degeneration) is the main pathological basis of LDH (lumbar disc herniation). ERS (endoplasmic reticulum stress) and UPR (unfolded protein response) may be key links connecting abnormal mechanics, nutritional disorders, oxidative stress, and inflammatory microenvironment with disc cell fate imbalance. This article reviews the roles of PERK, IRE1α and ATF6 UPR pathways in nucleus pulposus, annulus fibrosus and cartilage endplate, focusing on the evolution of LIDD to LDH. Existing studies have shown that moderate UPR helps to maintain protein homeostasis and promote extracellular matrix synthesis. Persistent or excessive ERS induces apoptosis, pyroptosis, necroptosis, ferroptosis, autophagy imbalance and senescence, through CHOP, JNK/NF-κB, NLRP3 inflammasome, mitochondrial damage and Ca2+ homeostasis disorder, resulting in decreased expression levels of Aggrecan and COL2A1. The expression levels of MMPs and ADAMTSs are increased, which lead to dehydration of nucleus pulposus, destruction of annulus fibrosus barrier and dystrophy of cartilage endplate, and may be involved in immune inflammation, tissue absorption and pain sensitization after protrusion. Chemical chaperones, UPR pathway modulation, antioxidant and mitochondrial protection, exosome-based therapies, and biomaterial-mediated local delivery have shown therapeutic potential, although current evidence is largely limited to in vitro and animal studies. In the future, it is necessary to combine with the validation based on human tissue stages and partitions, clarify the time phase and threshold of ERS, and establish an accurate local delivery and clinical transformation path.
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