Praelolide alleviates collagen-induced arthritis through increasing catalase activity and activating Nrf2 pathway

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BackgroundMarine diterpenes represent a promising reservoir for identifying potential anti-rheumatoid arthritis (RA) candidates. Praelolide is a gorgonian-derived briarane-type diterpenoid with antioxidative and anti-osteoclastogenetic properties. ObjectiveThis study aims to evaluate the therapeutic efficacy of praelolide against RA and investigate its underlying mechanisms both in vivo and in vitro. MethodCollagen-induced arthritis (CIA) mice and human RA fibroblast-like synoviocyte MH7A cells were employed for bioassays. The VisuGait system was utilized to assess gait dysfunction resulting from joint pain. Histopathological changes in ankle and synovial tissues were evaluated using micro-computed tomography, hematoxylin and eosin staining, Safranin-O/Fast Green staining, tartrate resistant acid phosphatase staining, and immunohistochemistry. Fluorescence spectroscopy, circular dichroism, and surface plasmon resonance were employed to investigate interactions between praelolide and catalase. The production of inflammatory cytokines and expression levels of proteins were assessed using ELISA and Western blotting, respectively. ResultPraelolide significantly reduced paw swelling and arthritis scores, improved gait deficits, and restored synovial histopathological alterations and bone erosion in CIA mice. In vivo and in vitro, praelolide effectively decreased the expression and production of inflammatory cytokines such as interleukin (IL)-1β and IL-6. Additionally, praelolide inhibited osteoclastogenesis on bone surface of the ankle joints and in a tumor necrosis factor-α (TNF-α)-induced MH7A/bone marrow-derived macrophages (BMMs) co-culture system, and it strongly suppressed reactive oxygen species (ROS) production. Mechanistically, praelolide modulated catalase through non-covalent interactions, inducing conformational alterations that enhanced catalase activity and stability against time- and temperature-induced degradation. Further investigation revealed that praelolide significantly upregulated the expression of Nrf2, subsequently activating downstream antioxidant enzymes. ConclusionPraelolide markedly alleviated synovial inflammation and bone destruction in CIA mice by enhancing catalase activity and activating the Nrf2 pathway to reduce disease-related ROS accumulation, highlighting praelolide as a promising candidate for multitarget treatment of RA.