How pH is regulated during amelogenesis in dental fluorosis.

Amelogenesis is a complicated process that concerns the interaction between growing hydroxyapatite crystals and extracellular proteins, which requires the tight regulation of pH. In dental fluorosis, the balance of pH regulation is broken, leading to abnormal mineralization. The current review focuses on the electrolyte transport processes associated with pH homeostasis, particularly regarding the changes in ion transporters that occur during amelogenesis, following exposure to excessive fluoride. Furthermore, the possible mechanism of fluorosis is discussed on the basis of acid hypothesis. There are two main methods by which F- accelerates crystal formation in ameloblasts. Firstly, it induces the release of protons, lowering the pH of the cell microenvironment. The decreased pH stimulates the upregulation of ion transporters, which attenuates further declines in the pH. Secondly, F- triggers an unknown signaling pathway, causing changes in the transcription of ion transporters and upregulating the expression of bicarbonate transporters. This results in the release of a large amount of bicarbonate from ameloblasts, which may neutralize the pH to form a microenvironment that favors crystal nucleation. The decreased pH stimulates the diffusion of F- into the cytoplasm of amelobalsts along the concentration gradient formed by the release of protons. The retention of F- causes a series of pathological changes, including oxidative and endoplasmic reticulum stress. If the buffering capacity of ameloblasts facing F- toxicity holds, normal mineralization occurs; however, if F- levels are high enough to overwhelm the buffering capacity of ameloblasts, abnormal mineralization occurs, leading to dental fluorosis.