Low back pain (LBP) is a pervasive global health concern, primarily associated with intervertebral disc (IVD) degeneration. Although oxidative stress has been shown to contribute to IVD degeneration, the underlying mechanisms remain undetermined. This study aimed to unravel the role of superoxide dismutase 2 (SOD2) in IVD pathogenesis and target oxidative stress to limit IVD degeneration. SOD2 demonstrated a dynamic regulation in surgically excised human IVD tissues, with initial upregulation in moderate degeneration and downregulation in severely degenerated IVDs. Through a comprehensive set of in vitro and in vivo experiments, we found a suggestive association between excessive mitochondrial superoxide, cellular senescence, and matrix degradation in human and mouse IVD cells. We confirmed that aging and mechanical stress, established triggers for IVD degeneration, escalated mitochondrial superoxide levels in mouse models. Critically, chondrocyte-specific deficiency accelerated age-related and mechanical stress-induced disc degeneration in mice, and could be attenuated by β-nicotinamide mononucleotide treatment. These revelations underscore the central role of SOD2 in IVD redox balance and unveil potential therapeutic avenues, making SOD2 and mitochondrial superoxide promising targets for effective LBP interventions.

中文翻译：

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SOD2 协调椎间盘中的氧化还原稳态：对氧化应激介导的退化和治疗潜力的新见解

腰痛 (LBP) 是一个普遍存在的全球健康问题，主要与椎间盘 (IVD) 退变有关。尽管氧化应激已被证明会导致 IVD 变性，但其潜在机制仍不清楚。本研究旨在揭示超氧化物歧化酶 2 (SOD2) 在 IVD 发病机制中的作用，并针对氧化应激来限制 IVD 退化。 SOD2 在手术切除的人类 IVD 组织中表现出动态调节，在中度退化的 IVD 中最初上调，在严重退化的 IVD 中下调。通过一系列全面的体外和体内实验，我们发现人和小鼠 IVD 细胞中过量的线粒体超氧化物、细胞衰老和基质降解之间存在暗示性关联。我们证实，衰老和机械应激是 IVD 变性的触发因素，会导致小鼠模型中线粒体超氧化物水平升高。至关重要的是，软骨细胞特异性缺陷加速了小鼠中与年龄相关和机械应力诱导的椎间盘退变，并且可以通过β-烟酰胺单核苷酸治疗来减轻。这些发现强调了 SOD2 在 IVD 氧化还原平衡中的核心作用，并揭示了潜在的治疗途径，使 SOD2 和线粒体超氧化物成为有效 LBP 干预的有希望的目标。