Well-defined alginate oligosaccharides ameliorate joint pain and inflammation in a mouse model of gouty arthritis

Background: Gouty arthritis causes severe pain and inflammation.Alginate oligosaccharides (AOSs) are natural products derived from alginate and have anti-inflammatory properties.We explored the potential effects of AOSs with different degrees of polymerization (Dp) on gouty arthritis and associated mechanisms. Methods:We established a mouse model of gouty arthritis by injecting monosodium urate (MSU) into ankle joint.Nocifensive behavior, gait and ankle swelling were used to study AOS's effects.Biochemical assays, in vivo imaging, live cell Ca 2+ imaging, electrophysiology, RNA-sequencing, etc. were used for mechanism exploration.Results: AOS2 (Dp=2), AOS3 (Dp=3) and AOS4 (Dp=4) all inhibited ankle swelling, whereas AOS2&3 produced the most obvious analgesia on model mice.AOS3, which was picked for further evaluation, produced dose-dependent ameliorative effects on model mice.AOS3 reversed gait impairments but did not alter locomotor activity.AOS3 inhibited NLRP3 inflammasome activation and inflammatory cytokine up-regulation in ankle joint.AOS3 ameliorated MSU-induced oxidative stress and reactive oxygen species (ROS) production both in vivo and in vitro and reversed the impaired mitochondrial bioenergetics.AOS3 activated the Nrf2 pathway and promoted Nrf2 disassociation from Keap1-bound complex and Nrf2 nuclear translocation, thus facilitating antioxidant gene expression via Nrf2-dependent mechanism.Nrf2 gene deficiency abolished AOS3's ameliorative effects on pain, inflammation and oxidative stress in ankle joints of model mice.AOS3 reduced TRPV1 functional enhancement in DRG neurons and constrained neuroactive peptide release.Conclusions: AOS3 ameliorates gouty arthritis via activating Nrf2-dependent antioxidant signaling, resulting in suppression of ROS-mediated NLRP3 inflammasome activation and TRPV1 enhancement.AOS3 may be novel therapeutics for gouty arthritis.