HIF-1α-mediated autophagy and canonical Wnt/β-catenin signalling activation are involved in fluoride-induced osteosclerosis in rats

Fluoride (F) exposure can cause osteosclerosis, which is characterised by a high bone mass, but its mechanism is not fully illustrated. Here, we aimed to evaluate the effects of excessive F exposure on the bone lesion by treating female Sprague-Dawley rats with different concentrations of sodium fluoride (NaF) (0, 55, 110 and 221 mg/L) for 90 days and the corresponding concentrations of fluorine ion (0, 25, 50 and 100 mg/L, respectively). Histopathological results showed that excessive F exposure caused the enlargement of trabeculae and their integration into one large piece, growth plate thickening, articular cartilage impairment and bone collagen abnormality. Meanwhile, F promoted calcium deposition and bone mineralisation, and induced abnormal osteogenesis increased. The results of micro-computed tomography also confirmed that excessive F destroyed the bone microstructure and induced a high-bone-mass phenotype, consistent with the results of pathomorphology. Mechanistically, excessive amounts of F led to angiogenesis inhibition and HIF-1α signalling enhancement. Subsequently, F induced autophagy and canonical Wnt/β-catenin signalling pathway activation. Collectively, these results manifested that F enhanced the hypoxia inducible factor-1α signalling, which in turn triggered autophagy and canonical Wnt/β-catenin signalling activation, ultimately leading to osteosclerosis in the rats.