TGF-β1 autocrine signalling and enamel matrix components

Transforming growth factor-beta 1 (TGF-beta 1) is present in porcine enamel extracts and is critical for proper mineralization of tooth enamel. Here, we show that the mRNA of latent TGF-beta 1 is expressed throughout amelogenesis. Latent TGF-beta 1 is activated by matrix metalloproteinase 20 (MMP20), coinciding with amelogenin processing by the same proteinase. Activated TGF-beta 1 binds to the major amelogenin cleavage products, particularly the neutral-soluble P103 amelogenin, to maintain its activity. The P103 amelogenin-TGF-beta 1 complex binds to TGFBR1 to induce TGF-beta 1 signalling. The P103 amelogenin-TGF-beta 1 complex is slowly cleaved by kallikrein 4 (KLK4), which is secreted into the transition-and maturation-stage enamel matrix, thereby reducing TGF-beta 1 activity. To exert the multiple biological functions of TGF-beta 1 for amelogenesis, we propose that TGF-beta 1 is activated or inactivated by MMP20 or KLK4 and that the amelogenin cleavage product is necessary for the in-solution mobility of TGF-beta 1, which is necessary for binding to its receptor on ameloblasts and retention of its activity.