Bisphosphonate Suppresses the Epithelial–Mesenchymal Transition of Post‐Tooth Extraction Oral Epithelial Cells via Direct and Indirect Pathways

ABSTRACT Purpose Bisphosphonate‐related osteonecrosis of the jaw is thought to be caused by inhibition of osteoclasts, but according to recent research, it has become known that bisphosphonates affect not only osteoclasts but also immune cells and other cells. However, the direct effects of bisphosphonates on the immune system of the mucous membrane covering the bone and oral tissue are not clear. Methods Using oral mucosal cell lines, we observed the effects of TGF‐β released from bone due to osteoclast‐mediated bone resorption during tooth extraction on oral mucosal cells in vivo and in vitro. These growth factors promote epithelial–mesenchymal transition (EMT) in oral mucosal cells and induce healing of the extraction site. Results TGF‐β is released from bone due to osteoclast‐mediated bone resorption, but bisphosphonates inhibit osteoclast activity, thereby potentially indirectly inhibiting EMT by blocking the activity of the Smad pathway, a downstream target of TGF‐β signaling. Additionally, bisphosphonates increase the expression of the autophagy marker Beclin, suggesting the influence of autophagy on bone metabolism. Conclusion In this study, administering bisphosphonate agents during tooth extraction, particularly during osteoporosis treatment, may prevent the onset of BRONJ by temporarily increasing local TGF‐β levels.