Understanding the mechanisms and implications of acacetin in mitigating diabetic osteoporosis: Insights from a zebrafish model

Osteoporosis, a condition characterised by reduced bone mineral density is more prevalent in individuals with diabetes. Acacetin, a natural flavonoid, possesses anti-inflammatory and antioxidant properties. However, its protective role in diabetic osteoporosis remains unexplored. Hence, the present study aimed to investigate the antihyperglycemic, antioxidant, and osteoprotective effects of acacetin using streptozotocin (STZ)-induced diabetic osteoporosis models in larval and adult zebrafish. The larvae were subjected to assays such as embryotoxicity, detection of oxidative stress markers (reactive oxygen species (ROS), superoxide levels, lipid peroxidation), apoptosis, and gene expression related to diabetes and osteoporosis. In adult zebrafish, body weight, blood glucose level, alkaline phosphatase, and tartrate resistant acid phosphatase (TRAP) activity were estimated, along with assays like alizarin red staining, histopathology, and gene expression. Interaction of acacetin and RANK/RANKL/OPG pathway was detected using molecular docking analysis. Acacetin exhibited antihyperglycemic effects in the zebrafish model, as shown by reduced blood glucose levels and increased body weight. Acacetin also demonstrated antioxidant properties by decreasing ROS, superoxide radicals, and lipid peroxidation levels. Additionally, acacetin treatment resulted in reduction of apoptosis and tartrate-resistant acid phosphatase levels and improved bone histology with increased bone density and enhanced alkaline phosphatase activity. In gene expression analysis, acacetin treatment has upregulated osteoprotegerin gene and downregulated RANKL gene. In conclusion, acacetin holds potential as a therapeutic agent for diabetic osteoporosis by targeting hyperglycemia, oxidative stress, apoptosis, and the RANK/RANKL/OPG signalling pathway.