Deletion of Dentin Matrix Protein-1 Leads to a Partial Failure of Maturation of Predentin into Dentin, Hypomineralization, and Expanded Cavities of Pulp and Root Canal during Postnatal Tooth Development

Abstract

The dentin matrix protein-1 (DMP-1) gene is identified in odontoblasts during both embryonic and postnatal development. In vitro study suggests that this noncollagen acidic phosphoprotein plays a role in mineralization. However, deletion of the Dmp-1 gene has little effect on tooth development during embryogenesis. To address the role of DMP-1 in tooth during postnatal development, we analyzed changes of dentinogenesis in Dmp-1 null mice from 3 days after birth to 1 year. Here we show that Dmp-1 null mice postnatally develop a profound tooth phenotype characterized by a partial failure of maturation of predentin into dentin, enlarged pulp chambers, increased width of predentin zone with reduced dentin wall, and hypomineralization. The tooth phenotype of these mice is strikingly similar to that in dentin sialophosphoprotein (Dspp) null mice and shares some features of the human disease dentinogenesis imperfecta III. We have also demonstrated that DSPP levels are reduced in Dmp-1 null mice, suggesting that DSPP is probably regulated by DMP-1 during dentinogenesis. Finally, we show the absence or delayed development of the third molar in Dmp-1 null mice, which is probably secondary to defects in Dmp-1 null bone. Taken together, these studies suggest that DMP-1 is essential for later dentinogenesis during postnatal development.Dentin is a mineralized tissue that closely resembles bone in composition and mechanism of formation. The mechanisms for mineralization are largely unclear, although two hypotheses are proposed to explain initiating mineralization: matrix vesicles in mantle dentin and collagen-phosphophoryn complexes in circumpulpal dentin (1). The in vitro studies also suggest that phosphorylated extracellular matrix (ECM) 1 proteins localized within collagen gap zones can bind calcium and phosphate ions in an appropriate conformation to nucleate the formation of apatite crystals (2, 3). One of the noncollagenous proteins that appears to play an important role in dentin ECM formation and mineralization is dentin matrix protein-1 (DMP-1).DMP-1, an acidic phosphorylated extracellular matrix protein (4), is expressed in odontoblasts that secrete matrix proteins to form dentin. Using protein chemistry approaches, some progress has been made in identifying the normally processed forms of DMP-1 in mineralized tissues (5). Although full-length DMP-1 has been cloned and sequenced, the corresponding intact protein has not been isolated from mineralized tissues. However, two proteolytic fragments, a 37-kDa N-terminal fragment and a 57-kDa C-terminal fragment, have been isolated from bone and dentin extracts (5). Recent studies suggest that DMP-1 can be cleaved by bone morphogenetic protein-1/tolloidlike proteinases (6).In vitro studies suggest that overexpression of Dmp-1 induces differentiation of mesenchymal cells to odontoblast-like cells and enhances mineralization (7) and that DMP-1 can bind to Ca 2ϩ and initiate mineral deposition in vitro (8). However, effects of recombinant DMP-1 on in vitro mineralization are ...

Immunohistochemical localization of dentin matrix protein 1 in human dentin

“…We have also found some DMP1 in the predentin/dentin transition areas (Figure 1 D) of the examined human teeth, mainly near the mineralization front.These findings are in agreement with the proposal that DMP1 has a role in the maturation of predentin matrix as confirmed by the presence of an expanded predentin layer in DMP1-null mice (Ye et al 2004). Interestingly, the group of Butler and co-workers (Baba et al 2004) followed changes in distribution of DMP1 during the sequential stages of rat molar development.…”

“…D entin matrix protein 1 (DMP1) is a multifunctional protein, prominent member of one category of non-collagenous proteins (NCPs), termed the SIBLINGS (Small IntegrinBinding Ligand, N-linked Glycoprotein), that regulates cell attachment and differentiation (Kulkarni et al 2000;Narayanan et al 2003), and plays a pivotal role in biomineralization (Ye et al 2004, reviewed in Qin et al 2007). George et al (1993) identified DMP1 by cDNA cloning and showed that it induces differentiation of mesenchymal cells into odontoblasts, and promotes mineralization.…”

Identification of Full-Length Dentin Matrix Protein 1 in Dentin and Bone

“…This purported biological function is supported by observations that MC3T3-E1 cells overexpressing DMP1 demonstrate an earlier onset of mineralization and the formation of a significantly larger size of the induced mineralized nodules compared to nontransfected control cells [4]. Findings from Dmp1 knockout mouse experiments and gene mutation studies on human osteomalacia strengthen the conclusion that DMP1 plays an important role in bone and dentin mineralization [5][6][7]. In addition to its direct role in biomineralization, studies indicated that DMP1 may regulate osteoblast-specific and/or odontoblast-specific genes [8,9].…”

Targeted expression of csCSF-1 in op/op mice ameliorates tooth defects

“…Lack of DMP1 expression in op/op teeth may have contributed to altered tooth morphology since op/op mice share a number of defects reported in DMP1 null pups including reduced enamel, widened predentin zone and decreased mineralized dentin. 36 The observation that DMP1 is markedly diminished in op/op odontoblasts is novel and suggests that CSF-1 may directly or indirectly regulate DMP1.…”