Purpose: This study aimed to explore the potential role and mechanism of garlic-derived S-allylmercaptocysteine (SAMC), the major water-soluble fraction of garlic, in osteoarthritis (OA) both in vivo and in vitro.
Methods: The effect of SAMC in a surgical-induced OA model was examined by X-ray, staining, ELISA, and immunoblotting. Then the key role of Nrf2 by SAMC treatment in IL-1β stimulated chondrocytes in vitro was determined by gene-knockdown technique.
Results: SAMC could stabilize the extracellular matrix (ECM) by decreasing metalloproteinase (MMPs) expression to suppress type II collagen degradation in OA rats. The inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, were elevated in OA, which could be down-regulated by SAMC treatment. This effect was parallel with NF-κB signaling inhibition by SAMC. As oxidative stress has been shown to participate in the inflammatory pathways in OA conditions, the key regulator Nrf2 in redox-homeostasis was evaluated in SAMC-treated OA rats. Nrf2 and its down-stream gene NQO-1 were activated in the SAMC-treated group, accompanied by NAD(P)H oxidases 4 (NOX4) expression down-regulated. As a result, the toxic lipid peroxidation byproduct 4-hydroxynonenal (4HNE) was reduced in articular cartilage. In IL-1β-stimulated primary rat chondrocytes, which could mimic OA in vitro, SAMC could ameliorate collagen destruction, inhibit inflammation, and maintain redox-homeostasis. Interestingly, after Nrf2 gene knockdown by adenovirus, the protective effect of SAMC in IL-1β-stimulated chondrocytes disappeared.
Conclusion: Overall, our study demonstrated that SAMC targeted Nrf2 to protect OA both in vivo and in vitro, which would be a new pharmaceutical way for OA therapy.

Keywords: S-allylmercaptocysteine, Nrf2, osteoarthritis, oxidative stress, inflammation


中文翻译：

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S-烯丙基巯基半胱氨酸通过 NOX4/NF-κB 通路靶向 Nrf2 治疗骨关节炎


目的：本研究旨在探讨大蒜衍生的 S-烯丙基巯基半胱氨酸 (SAMC)（大蒜的主要水溶性部分）在体内和体外治疗骨关节炎 (OA) 中的潜在作用和机制。

方法：通过 X 射线、染色、ELISA 和免疫印迹检查 SAMC 在手术诱导的 OA 模型中的作用。然后通过基因敲除技术确定了 SAMC 处理的 Nrf2 在体外 IL-1β 刺激的软骨细胞中的关键作用。

结果： SAMC 可以通过降低金属蛋白酶（MMP）表达来稳定细胞外基质（ECM），从而抑制 OA 大鼠的 II 型胶原降解。 OA 中炎症细胞因子（如 IL-1β、TNF-α 和 IL-6）升高，而 SAMC 治疗可下调这些细胞因子。这种效应与 SAMC 的 NF-κB 信号传导抑制作用平行。由于氧化应激已被证明参与 OA 条件下的炎症途径，因此在 SAMC 治疗的 OA 大鼠中评估了氧化还原稳态的关键调节因子 Nrf2。 SAMC治疗组中Nrf2及其下游基因NQO-1被激活，同时NAD(P)H氧化酶4(NOX4)表达下调。结果，关节软骨中有毒的脂质过氧化副产物4-羟基壬烯醛（4HNE）减少。在 IL-1β 刺激的原代大鼠软骨细胞中（可在体外模拟 OA），SAMC 可以改善胶原蛋白破坏、抑制炎症并维持氧化还原稳态。有趣的是，在腺病毒敲除Nrf2基因后，SAMC对IL-1β刺激的软骨细胞的保护作用消失。

结论：总体而言，我们的研究表明，SAMC 靶向 Nrf2 在体内和体外均可保护 OA，这将成为 OA 治疗的新药物途径。


关键词: S-烯丙基巯基半胱氨酸, Nrf2, 骨关节炎, 氧化应激, 炎症