Painful intervertebral disc degeneration and inflammation:from laboratory evidence to clinical interventions

Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration,a significant contributor to LBP.Inflammatory mediators also play an indispensable role in discogenic LBP.The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies.Here,an overview of the advances in inflammation-related pain in disc degeneration is provided,with a discussion on the role of inflammation in IVD degeneration and pain induction.Puncture models,mechanical models,and spontaneous models as the main animal models to study painful disc degeneration are discussed,and the underlying signaling pathways are summarized.Furthermore,potential drug candidates,either under laboratory investigation or undergoing clinical trials,to suppress discogenic LBP by eliminating inflammation are explored.We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.

Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop

The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin(IL)-1β, and is one of the main causes of intervertebral disc degeneration(IVDD). NLR pyrin domain containing 3(NLRP3) inflammasome activation is an important source of IL-1β. As an anti-inflammatory neuroendocrine hormone, melatonin plays various roles in different pathophysiological conditions. However, its roles in IVDD are still not well understood and require more examination. First, we demonstrated that melatonin delayed the progression of IVDD and relieved IVDD-related low back pain in a rat needle puncture IVDD model;moreover, NLRP3 inflammasome activation(NLRP3, p20, and IL-1β levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus(NP) cells that were treated with IL-1β. In these cells, expression of NLRP3 and p20 was significantly increased, NF-κB signaling was involved in this regulation, and mitochondrial reactive oxygen species(mt ROS)production increased. Furthermore, we found that melatonin disrupted the IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1β levels by inhibiting NF-κB signaling and downregulating mt ROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1β in vivo. In this study, we showed for the first time that IL-1β promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1β positive feedback loop and may be a potential therapeutic agent for IVDD.