Mechanism and cross-talk of signaling pathways associated with bone damage in fluorosis

Chronic fluorosis is a kind of chronic systemic disease. Bone damage in fluorosis is mainly manifested as skeletal fluorosis and dental fluorosis. Fluorine or fluoride can break the dynamic balance of bone turnover and induce the differentiation and apoptosis of osteoblasts/osteoclasts by affecting mutiple stages of signaling pathways. This review highlighted the roles of five signaling pathways: hedgehog, Wnt/β-catenin, Notch, receptor activator of nuclear factorkappa B/receptor activator of nuclear factor-kappa B ligand/osteoprotegerin, and parathyroid hormone (PTH), and the identified keynodes in these signaling pathways. It was found that fluoride can interfere with the molecular activity of selected signaling pathways, regulate bone turnover, and maintain bone formation and bone destruction during fluorosis through the synergistic or antagonistic action of pathways.