Osteoarthritis (OA) is an inflammatory disease of the joints that causes progressive disability in the elderly. Reactive oxygen species (ROS) play an important role in OA development; they may activate the NLRP3 inflammasome, thereby inducing the secretion of proinflammatory IL-1β and IL-18, leading to the aggravation of the downstream inflammatory response. Nrf2 is a key transcription factor that regulates the expression of antioxidant enzymes that protect against oxidative stress and tissue damage. We aimed to explore the underlying mechanism of OA development by investigating NLRP3, ASC, Nrf2, and HO-1 expression in synovia and their regulatory networks in OA. Human total knee replacement samples were subjected to histology and micro-CT analysis to determine the pathological changes in the cartilage and subchondral bone and to assess the expression of inflammation-related markers in the synovial tissue by immunohistochemistry (IHC), qRT-PCR, and Western blot. To investigate these pathological changes in an OA animal model, adult Sprague-Dawley rats were subjected to anterior cruciate ligament transection and medial meniscectomy. Articular cartilage and subchondral bone changes and synovial tissue were also determined by the same methods used for the human samples. Finally, SW982 cells were stimulated with lipopolysaccharide (LPS) as an in vitro inflammatory cell model. The correlation between NLRP3 and Nrf2 expression was confirmed by knocking down NLRP3 or Nrf2. Cartilage destruction and subchondral bone sclerosis were found in the OA patients and OA model rats. Significantly increased expression levels of NLRP3, ASC, Nrf2, and HO-1 were found in the synovial tissue from OA patients. NLRP3, ASC, Nrf2, and HO-1 expression in the synovium was also upregulated in the OA group compared with the sham group. Furthermore, the NLRP3, Nrf2, HO-1, IL-1β, and IL-18 expression in LPS-treated SW982 cells was increased in a dose-dependent manner. As expected, the expression of NLRP3 was upregulated, and the expression of IL-1β and IL-18 was downregulated after Nrf2 silencing. However, knocking down NLRP3 did not affect the expression of Nrf2. ROS-induced oxidative stress may be the main cause of NLRP3 inflammasome activation and subsequent release of downstream factors during OA development. Nrf2/HO-1 signaling could be a key pathway for the activation of the NLRP3 inflammasome, which may contribute to the progression of OA. Herein, we discovered a novel role of Nrf2/HO-1 signaling in the production of NLRP3, which may facilitate the prevention and treatment of OA.

中文翻译：

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Nrf2 / HO-1信号的抑制导致骨关节炎中NLRP3炎性小体的激活增加

骨关节炎（OA）是一种关节发炎性疾病，可导致老年人进行性残疾。活性氧（ROS）在OA的发展中起着重要的作用。它们可能激活NLRP3炎性体，从而诱导促炎性IL-1β和IL-18的分泌，从而加剧下游炎症反应。Nrf2是调节抗氧化酶表达的关键转录因子，该抗氧化酶可防止氧化应激和组织损伤。我们旨在通过研究滑膜中的NLRP3，ASC，Nrf2和HO-1表达及其在OA中的调控网络来探索OA发展的潜在机制。对人类全膝关节置换样品进行组织学和显微CT分析，以确定软骨和软骨下骨的病理变化，并通过免疫组化（IHC），qRT-PCR和滑膜组织评估炎症相关标志物在滑膜组织中的表达。蛋白质印迹。为了研究OA动物模型中的这些病理变化，对成年的Sprague-Dawley大鼠进行了前交叉韧带横断和半月板内侧切除术。关节软骨和软骨下骨的变化以及滑膜组织也通过与人类样品相同的方法进行测定。最后，用脂多糖（LPS）刺激SW982细胞作为体外炎症细胞模型。通过敲低NLRP3或Nrf2，证实了NLRP3和Nrf2表达之间的相关性。在OA患者和OA模型大鼠中发现软骨破坏和软骨下骨硬化。在OA患者的滑膜组织中发现NLRP3，ASC，Nrf2和HO-1的表达水平显着增加。与假手术组相比，OA组滑膜中的NLRP3，ASC，Nrf2和HO-1表达也上调。此外，LPS处理的SW982细胞中NLRP3，Nrf2，HO-1，IL-1β和IL-18的表达呈剂量依赖性。不出所料，Nrf2沉默后，NLRP3的表达上调，而IL-1β和IL-18的表达下调。但是，敲低NLRP3不会影响Nrf2的表达。ROS诱导的氧化应激可能是NLRP3炎性小体活化以及OA发育过程中下游因子随后释放的主要原因。Nrf2 / HO-1信号可能是激活NLRP3炎性小体的关键途径，这可能有助于OA的发展。在本文中，我们发现了Nrf2 / HO-1信号转导在NLRP3产生中的新作用，这可能有助于OA的预防和治疗。