Chitosan‑selenium nanoparticles mitigate fluoride-induced bone injury by regulating OPG/RANKL/NF-κB pathway through the gut-bone axis

Excessive fluoride intake can lead to skeletal fluorosis, which is a global public health concern. In recent years, selenium-loaded chitosan nanoparticles (CS-SeNPs) have attracted considerable attention due to their high bioactivity and favourable adhesion to the intestinal mucosa, and have demonstrated significant potential in mitigating skeletal damage. Nevertheless, it remains unclear whether CS-SeNPs can improve fluoride-induced bone damage and what the underlying regulatory mechanisms are. In this study, we found that CS-SeNPs alleviated fluoride-induced intestinal barrier disruption and colonic microbiota dysbiosis by downregulating pro-inflammatory and toxin-producing bacteria Desulfovibrio and Bilophila. CS-SeNPs increased the levels of beneficial bacteria such as Lactobacillus and Blautia, suppressed the expression of tumor necrosis factor (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), and reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels, thereby improving systemic chronic inflammation and oxidative damage. Furthermore, CS-SeNPs also enhanced the absorption of calcium and phosphorus by bone tissue and, via the gut-bone axis, inhibited the sustained activation of the bone osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/nuclear factor kappa-B (NF-κB) pathway, as well as the abnormal activation of osteoclasts, thereby restoring bone metabolic balance and effectively alleviating fluoride-induced bone damage. These findings reveal the unique mechanisms of CS-SeNPs in regulating bone resorption and bone formation, not only providing new insights into the interaction between CS-SeNPs and the intestinal microbiota, but also offering potential therapeutic strategies for alleviating fluoride-induced bone damage.