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Chronic exposure to combined fluoride (F) and arsenic (As) continues to be a major public health problem worldwide, attracting the attention of an increasing number of researchers. While bone is the main target organ of syndrome of endemic arsenic poisoning and fluorosis (SEAF), the specific mechanism and targeted intervention remains uncertain. The first question in this study sought to determine the interaction of F and As on the Wnt signaling pathway and its role in osteogenic differentiation in the SEAF population. As can be seen from the data, with the increase in exposure to F, the content of Wnt signaling inhibitor Dickkopf-related protein 1 (DKK1) gradually decreased, but the expression of glycogen synthase kinase-3β (GSK3β), β-catenin and the osteogenic differentiation indicators pro-collagen I alpha 1 (COL1A1) and bone alkaline phosphatase (BALP) were increased. Next, we grouped the SEAF population according to urinary As and found that As can upregulate the GSK3β, β-catenin level and the bone formation bio-marker BALP in serum. But the experiments did not detect any evidence that As can change the content of DKK1 in serum. To better understand the combined effects of F and As on the Wnt signaling pathway, we performed further interaction analysis. These results suggest that the interaction of F and As can inhibit the GSK3β, β-catenin, COL1A1 and BALP. And DKK1 is mainly manifested by the independent effect of F. To further study the role of DKK1 and GSK3β in fluoride-arsenic pollution combined with osteogenic differentiation, we attempted to silence the DKK1 and GSK3β gene in hFOB 1.19 cells. The results show that F, As alone and in combination exposure can up-regulate GSK catenin transcription and protein expression levels and down-regulate DKK1, and COL1A1 and ALP are significantly increased, after silenced the DKK1. The same results did not appear after silenced the GSK3β. F and As alone and in combination exposure did not reverse the inhibition of GSK3β and β-catenin by GSK3β silencing, and COL1A1 and ALP are significantly decreased. The results indicate that silencing GSK3β instead of DKK1 can inhibit osteogenic differentiation caused by co-exposure to fluoride and arsenic. This study can provide a scientific basis for further understanding the causes of bone formation caused by F and As and the improvement of targeted intervention strategies. Unlabelled Image • Wnt signaling is involved in the osteogenic differentiation caused by co-exposure to F and As. • Silencing GSK3β can inhibit osteogenic differentiation caused by co-exposure to F and As. • Silencing DKK1 cannot inhibit osteogenic differentiation caused by co-exposure to F and As. • The interaction between F and As of the Wnt signaling occurs mainly as antagonism. [ABSTRACT FROM AUTHOR]