State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
Drum Tower of Clinical Medicine, Nanjing Medical University, Nanjing, 210008, China.
Acta Pharmacol Sin. 2022 Feb;43(2):417-428. doi: 10.1038/s41401-021-00646-z. Epub 2021 Apr 8.
Oxidative stress-related cartilage degeneration, synovitis, and joint pain play vital roles in the progress of osteoarthritis (OA). Anti-oxidative stress agents not only prevent structural damage progression but also relieve OA-related pain. In this study, we investigated the therapeutic effect of methylene blue (MB), a classical and important anti-oxidant with strong neural affinity. Experimental OA was established in rats by radial transection of medial collateral ligament and medial meniscus (MCLT + MMT) of the right knee joint. The OA rats received intra-articular injection of MB (1 mg/kg) every week starting one week after surgery. We showed that MB administration exerted significant cartilage protection, synovitis inhibition as well as pain relief in OA rats. In human chondrocytes and fibroblast-like synoviocytes, MB significantly attenuated tert-butyl hydroperoxide (TBHP)-induced inflammatory response and oxidative stress. We demonstrated that these effects of MB resulted from dual targets of important antioxidant enzymes, Nrf2 and PRDX1, which also mutually reinforcing and participated in an interaction. Furthermore, we found that calcitonin gene-related peptide (CGRP), a neural inflammatory mediator, was accumulated around the vessel in synovium and subchondral bone in OA rats and in TBHP-treated primary cortical neurons; MB administration significantly inhibited CGRP expression through upregulation of Nrf2 and PRDX1. Taken together, these results suggest that MB ameliorates oxidative stress via Nrf2/PRDX1 regulation to prevent progression and relieve pain of OA.
氧化应激相关的软骨退变、滑膜炎和关节痛在骨关节炎（OA）的进展中起着至关重要的作用。抗氧化应激剂不仅可以预防结构损伤的进展，还可以缓解 OA 相关的疼痛。在这项研究中，我们研究了亚甲蓝（MB）的治疗效果，亚甲蓝是一种具有很强神经亲和力的经典和重要的抗氧化剂。通过对右膝关节内侧副韧带和内侧半月板（MCLT+MMT）的横断，在大鼠中建立实验性 OA。OA 大鼠在手术后一周开始每周接受一次关节内注射 MB（1mg/kg）。我们发现 MB 给药在 OA 大鼠中表现出显著的软骨保护、滑膜炎抑制和疼痛缓解作用。在人软骨细胞和成纤维样滑膜细胞中，MB 显著减弱了叔丁基过氧化物（TBHP）诱导的炎症反应和氧化应激。我们证明，MB 的这些作用是由重要抗氧化酶 Nrf2 和 PRDX1 的双重靶点产生的，这两个靶点也相互加强并参与相互作用。此外，我们发现降钙素基因相关肽（CGRP），一种神经炎症介质，在 OA 大鼠和 TBHP 处理的原代皮质神经元的滑膜和软骨下骨中围绕血管积累；MB 给药通过上调 Nrf2 和 PRDX1 显著抑制 CGRP 的表达。总之，这些结果表明，MB 通过 Nrf2/PRDX1 调节来改善氧化应激，从而预防 OA 的进展并缓解疼痛。
