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Chronic intermittent hypobaric hypoxia alleviates early-stage posttraumatic osteoarthritis via NF-κB/Nrf2 pathway in
Guowei Ren1, Lindan Geng1, Dong Ren1
1Department of Orthopaedic Trauma, Hebei Medical University Third Hospital, Ziqiang Road No.139, Shijiazhuang, Hebei Province, 050051, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Chronic intermittent hypobaric hypoxia (CIHH) treatment immediately after joint injury delays posttraumatic osteoarthritis (PTOA) progression. This therapy activates Nrf2 and inhibits NF-κB signaling, reducing inflammation and cartilage damage.
Area of Science:
- Orthopedics
- Regenerative Medicine
- Biochemistry
Background:
- Posttraumatic osteoarthritis (PTOA) arises from acute articular cartilage injury.
- Early intervention post-injury is crucial for inhibiting cartilage destruction and slowing PTOA.
- The therapeutic potential of chronic intermittent hypobaric hypoxia (CIHH) in acute cartilage injury is largely unexplored.
Purpose of the Study:
- To investigate the protective effects of CIHH on cartilage immediately following acute injury.
- To elucidate the molecular mechanisms underlying CIHH's impact on cartilage at different time points.
- To identify potential therapeutic targets for PTOA in the acute injury phase.
Main Methods:
- A non-invasive PTOA mouse model was induced via tibial plateau impact.
- Mice received immediate CIHH treatment (5000m altitude mimic) post-injury.
- Evaluations included Safranin O-Fast Green staining, immunohistochemistry, ELISA, and Western blotting over 28 days.
- NF-κB p65 and Nrf2 nuclear translocation were assessed via immunofluorescence.
Main Results:
- CIHH treatment significantly delayed PTOA progression and reduced Mankin scores.
- Proinflammatory factors (iNOS, NO, TNF-α, IL-1β) and catabolic enzymes (ADAMTS5, MMP13) were suppressed.
- CIHH reversed degradation of Collagen II and COMP, and decreased ROS levels, indicating reduced oxidative stress.
- CIHH activated Nrf2 and inhibited NF-κB signaling.
Conclusions:
- Immediate CIHH treatment attenuates load-induced cartilage damage in PTOA.
- The mechanism involves activating Nrf2/HO-1 and inhibiting NF-κB p65 pathways.
- CIHH counteracts oxidative stress and inflammation, enhancing cartilage matrix balance and delaying degeneration.
- This approach shows promise as a therapeutic strategy for limiting PTOA progression.
