Abstract
BackgroundMatrix metalloproteinase-20 (Mmp20) ablated mice have enamel that is thin and soft with an abnormal rod pattern that abrades from the underlying dentin. We asked if introduction of transgenes expressing Mmp20 would revert this Mmp20 null phenotype back to normal. Unexpectedly, for transgenes expressing medium or high levels of Mmp20, we found opposite enamel phenotypes depending on the genetic background (Mmp20−/− or Mmp20+/+) in which the transgenes were expressed.Methodology/Principal Findings Amelx-promoter-Mmp20 transgenic founder mouse lines were assessed for transgene expression and those expressing low, medium or high levels of Mmp20 were selected for breeding into the Mmp20 null background. Regardless of expression level, each transgene brought the null enamel back to full thickness. However, the high and medium expressing Mmp20 transgenes in the Mmp20 null background had significantly harder more mineralized enamel than did the low transgene expresser. Strikingly, when the high and medium expressing Mmp20 transgenes were present in the wild-type background, the enamel was significantly less well mineralized than normal. Protein gel analysis of enamel matrix proteins from the high and medium expressing transgenes present in the wild-type background demonstrated that greater than normal amounts of cleavage products and smaller quantities of higher molecular weight proteins were present within their enamel matrices.Conclusions/Significance Mmp20 expression levels must be within a specific range for normal enamel development to occur. Creation of a normally thick enamel layer may occur over a wider range of Mmp20 expression levels, but acquisition of normal enamel hardness has a narrower range. Since over-expression of Mmp20 results in decreased enamel hardness, this suggests that a balance exists between cleaved and full-length enamel matrix proteins that are essential for formation of a properly hardened enamel layer. It also suggests that few feedback controls are present in the enamel matrix to prevent excessive MMP20 activity.
Highlights
Dental enamel is the hardest tissue of the body, but it does not start that way
Three transgenic founder mice were selected based on the ability of their incisor enamel organs to express low (Tg42), intermediate (Tg6) or high (Tg24) levels of Matrix metalloproteinase-20 (Mmp20) transgene transcripts in the Mmp20 null background (Fig. 1A)
We performed qPCR on incisor enamel organs to confirm that the total level of wild-type and transgene Mmp20 transcripts were increased when the transgenes were present in the wild-type background (Fig. 1B)
Summary
Dental enamel is the hardest tissue of the body, but it does not start that way. Enamel development (amelogenesis) can be defined as consisting of three stages; the secretory, transition, and maturation stages [1]. During the secretory stage the ameloblasts adjacent to the forming enamel elongate and secrete large quantities of protein into the enamel matrix. During the subsequent maturation stage, the short columnar ameloblasts reabsorb the proteins they had previously secreted. This is when the enamel ribbons grow to their greatest amount in width and thickness [1]. Defective thin (hypoplastic) enamel suggests a developmental deficiency during the secretory stage when the crystallite ribbons are lengthening to establish the full thickness of the enamel layer. Erupted teeth with enamel that has reached full thickness, but is soft and not well mineralized (hypomaturation) suggests a developmental deficiency during the maturation stage when the crystallite ribbons grow in width and thickness and interlock. For transgenes expressing medium or high levels of Mmp, we found opposite enamel phenotypes depending on the genetic background (Mmp202/2 or Mmp20+/+) in which the transgenes were expressed
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