Ren Guowei, Geng Lindan, Ren Dong, Hou Haowei, Yao Shuangquan, Shi Zhenhua, Wang Pengcheng
Department of Orthopaedic Trauma, Hebei Medical University Third Hospital, Ziqiang Road No.139, Shijiazhuang, Hebei Province, 050051, China.
Department of Scientific Research, Hebei Medical University Third Hospital, Shijiazhuang, Hebei Province, 050051, China.
J Orthop Surg Res. 2024 Dec 26;19(1):878. doi: 10.1186/s13018-024-05376-6.
Posttraumatic osteoarthritis (PTOA) is directly associated with early acute articular cartilage injury. Inhibition of cartilage destruction immediately following joint damage can effectively slow or prevent PTOA progression. Therefore, we sought to determine intervention targets and therapeutic strategies in the acute stage of cartilage injury. The benefits of chronic intermittent hypobaric hypoxia (CIHH) extend to various body tissues, but its impact on acute cartilage injury remains unclear. We selected PTOA initiation as the therapeutic window and administered CIHH treatment immediately following cartilage injury initiation to investigate its protective effect on cartilage and molecular mechanism changing with time-varying.
The non-invasive PTOA mouse model was established by applying a single rapid specific impact force to the right knee's tibial plateau, initiating load-induced PTOA development, closely resembling the pathological changes in human diseases. Following loading, we inhibited cartilage destruction by treating mice immediately in a hypobaric chamber with a hypobaric hypoxia mimic at 5000 m altitude. Cohorts of mice subjected to distinct experimental conditions were monitored for 3, 7, 14 or 28 days. Safranin O-Fast Green staining, Immunohistochemistry, immunofluorescence, ELISA, and western blotting were performed to evaluate the therapeutic effects of CIHH on cartilage in vivo. The nuclear translocation of NF-κB p65 and Nrf2 were detected by immunofluorescence.
The results showed that inhibiting cartilage destruction using CIHH immediately following acute articular cartilage injury initiation delayed the progression of PTOA, decreased the Mankin score and suppressed the expression of proinflammatory factors, including iNOS, NO, TNF-α, and IL-1β. Meanwhile, immediate CIHH treatment reduced levels of the catabolic enzymes ADAMTS5 and MMP13 in the cartilage matrix, reversed degradation of Collagen II and COMP, and inhibited oxidative stress by decreasing ROS levels. Moreover, CIHH suppressed NF-κB signaling by activating the Nrf2 in vivo studies.
Our study demonstrated that immediate CIHH treatment following cartilage injury initiation can attenuate load-induced cartilage damage by activating Nrf2/HO-1 and inhibiting the NF-κB p65 signalling pathways to counteract oxidative stress and inflammatory reactions, enhance the metabolic balance of the cartilage matrix and delay cartilage degeneration. This treatment may represent a potential therapeutic strategy for limiting PTOA progression.
创伤后骨关节炎（PTOA）与早期急性关节软骨损伤直接相关。在关节损伤后立即抑制软骨破坏可有效减缓或阻止PTOA的进展。因此，我们试图确定软骨损伤急性期的干预靶点和治疗策略。慢性间歇性低压低氧（CIHH）的益处延伸至身体各个组织，但其对急性软骨损伤的影响仍不清楚。我们选择PTOA发病作为治疗窗口，并在软骨损伤开始后立即给予CIHH治疗，以研究其对软骨的保护作用以及随时间变化的分子机制。
通过对右膝胫骨平台施加单次快速特定冲击力建立非侵入性PTOA小鼠模型，引发负荷诱导的PTOA发展，这与人类疾病的病理变化极为相似。加载后，我们通过在低压舱中用模拟5000米海拔的低压低氧环境立即处理小鼠来抑制软骨破坏。对处于不同实验条件下的小鼠队列进行3、7、14或28天的监测。进行番红O-固绿染色、免疫组织化学、免疫荧光、酶联免疫吸附测定（ELISA）和蛋白质免疫印迹法以评估CIHH对体内软骨的治疗效果。通过免疫荧光检测NF-κB p65和Nrf2的核转位。
结果表明，在急性关节软骨损伤开始后立即使用CIHH抑制软骨破坏可延缓PTOA的进展，降低曼金评分，并抑制促炎因子的表达，包括诱导型一氧化氮合酶（iNOS）、一氧化氮（NO）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）。同时，立即进行CIHH治疗可降低软骨基质中分解代谢酶ADAMTS5和基质金属蛋白酶13（MMP13）的水平，逆转Ⅱ型胶原蛋白（Collagen II）和软骨寡聚基质蛋白（COMP）的降解，并通过降低活性氧（ROS）水平抑制氧化应激。此外，在体内研究中，CIHH通过激活Nrf2抑制NF-κB信号传导。
我们的研究表明，在软骨损伤开始后立即进行CIHH治疗可通过激活Nrf2/血红素加氧酶-1（HO-1）并抑制NF-κB p65信号通路来减轻负荷诱导的软骨损伤，以对抗氧化应激和炎症反应，增强软骨基质的代谢平衡并延缓软骨退变。这种治疗可能代表一种限制PTOA进展的潜在治疗策略。
