Matrix Metalloproteinase-20 Over-Expression Promotes Cell Invasion via WNT Signalling

Objectives: Matrix Metalloproteinase-20 (MMP20; enamelysin) is expressed in teeth. Mutations in MMP20 cause amelogenesis imperfecta and Mmp20 ablated mice have hypoplastic enamel that abrades from the underlying dentin. Transgenic mice that use the amelogenin promoter to drive Mmp20 expression (Mmp20Tg) in the Mmp20 ablated background, had a significant improvement in their enamel physical properties. Surprisingly, when the highly expressing transgene was present in the wild-type (WT) background, the enamel became malformed. We sought to determine how Mmp20 over-expression results in enamel malformation.
Methods: Mmp20Tg mice were characterized by western blots, histological analyses and qPCR.
Results: Incisors from Mmp20^+/+ mice expressing the Mmp20Tg had a massive cell infiltrate which occupied a large area within the enamel space. A very thin layer of enamel-like material remained over the dentin and at the outer enamel surface, but between these regions were numerous cells and ectopic bone-like calcifications containing type I collagen. Some ameloblasts within these mice remained recognizable in isolated areas of the cell infiltrate. The invading cells contained proliferating epithelial cells and fibroblasts. The Mmp20^+/+Tg mice had decreased enamel organ cadherin levels compared to the Mmp20 ablated and WT mice and, instead of predominantly locating adjacent to the ameloblast cell membrane, β-catenin was predominantly present within the nuclei of the invading cells.
Conclusions: MMP20 overexpression increased cadherin cleavage and β-catenin release from cadherin complexes. The released β-catenin appeared to translocate to ameloblast nuclei, which promoted cell migration/invasion. Therefore, we conclude that MMP20 plays a role in normal ameloblast migration through limited cadherin cleavage and resulting canonical WNT signaling. However, MMP20 overexpression increases WNT signaling and promotes a massive cell migration into the forming enamel layer.