TGF-β autocrine signaling at secretory-stage enamel

Abstract Background In recent years, transforming growth factor (TGF)-β has been found in the enamel matrix, and along with enamel protein, is thought to play an important role in the process of calcification of tooth enamel. The purpose of this study was to investigate the dynamics of TGF-β and its interactions with enamel proteins, through experiments at the genetic and protein levels. Highlights The expression of the latent TGF-β1 gene was observed during the enamel formation process. TGF-β1 was found in both immature and mature enamel, and its activity tended to decrease as immature enamel transitioned to mature enamel. In vitro studies showed that latent TGF-β1 was activated by matrix metalloproteinase 20 (MMP20), and activated TGF-β1 was degraded by kallikrein-4 (KLK4). By binding to the major amelogenins, activated TGF-β1 maintained its activity. Of the major amelogenins, the 13 kDa amelogenin had the highest affinity for activated TGF-β1. Moreover, the 13 kDa amelogenin-activated TGF-β1 complex was bound to the TGF-β1 receptor on the ameloblast cell surface and induced signaling. Conclusion Latent TGF-β1 produced and secreted from secretory-stage ameloblasts is activated by MMP20, and the activated TGF-β1 maintains its activity by combining with amelogenin cleavage products processed by the same protease. TGF-β1 moves through the aqueous phase with the water-soluble 13 kDa amelogenin and binds to its receptor on the ameloblast surface, thereby inducing autocrine signaling. Once the ameloblasts differentiate and enter the maturation stage, TGF-β1 is degraded by KLK4, which is produced and secreted by maturation-stage ameloblasts, and loses its activity.