Rescue of odontogenesis in Dmp1-deficient mice by targeted re-expression of DMP1 reveals roles for DMP1 in early odontogenesis and dentin apposition in vivo

Abstract

Dentin matrix protein 1 (DMP1) is expressed in both pulp and odontoblast cells and deletion of the Dmp1 gene leads to defects in odontogenesis and mineralization. The goals of this study were to examine how DMP1 controls dentin mineralization and odontogenesis in vivo. Fluorochrome labeling of dentin in Dmp1-null mice showed a diffuse labeling pattern with a 3-fold reduction in dentin appositional rate compared to controls. Deletion of DMP1 was also associated with abnormalities in the dentinal tubule system and delayed formation of the third molar. Unlike the mineralization defect in Vitamin D receptor-null mice, the mineralization defect in Dmp1-null mice was not rescued by a high calcium and phosphate diet, suggesting a different effect of DMP1 on mineralization. Re-expression of Dmp1 in early and late odontoblasts under control of the Col1a1 promoter rescued the defects in mineralization as well as the defects in the dentinal tubules and third molar development. In contrast, re-expression of Dmp1 in mature odontoblasts, using the Dspp promoter, produced only a partial rescue of the mineralization defects. These data suggest that DMP1 is a key regulator of odontoblast differentiation, formation of the dentin tubular system and mineralization and its expression is required in both early and late odontoblasts for normal odontogenesis to proceed.

Immunohistochemical localization of dentin matrix protein 1 in human dentin

“…While the immunohistochemical pattern of DMP1 has been clearly elucidated in mice dentin (Feng et al 2003;Lu et al 2007), no correlative TEM and fluorescence data have been available on human sound dentin. DMP1 accumulates along the peritubular dentin wall of human sound dentin, similarly to what has been previously reported in mice (Lu et al 2007), thus suggesting a functional role in their formation and maintenance (Baba et al 2004).…”

“…Cooperative interactions between DMP1 and type I collagen can initiate apatite nucleation and mineral deposition (He & George 2004, He et al 2005. Recently, in vivo studies by Lu and coworkers (Lu et al 2007) revealed that DMP1-null mice show abnormalities in mineralization and structural organization of dentin.…”

“…It immunolocalizes preferentially along the wall of dentinal tubules and in peritubular dentin (Massa et al 2005;Lu et al 2007). Recently, two studies on hypophosphatemic teeth of children have ana-lyzed presence of DMP1 in dentin by means of immunohistochemistry, showing that DMP1, like other NCPs, was localized in the inner third of circumpulpal dentin, associated with the tubular and intertubular dentin, whereas in hypophosphatemic teeth DMP1 was only observed in the dentin interglobular spaces (Boukpessi et al 2006;Chaussain-Miller et al 2007).…”

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

“…A full-length mouse DMP1 cDNA was obtained by digesting the DMP1-pBC-KS+ construct [9] with EcoRI restriction enzyme, and the released DMP1 cDNA fragment was subcloned into a mammalian expression vector, pcDNA3.1. The DMP1-pcDNA3.1 construct was used to transfect a human embryonic kidney cell line, HEK-293, or a murine preosteoblastic cell line, MC3T3-E1.…”

“…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]. More recent studies indicated that DMP1 may also be involved in the regulation of phosphate homeostasis through fibroblast growth factor 23 (FGF23), a newly identified hormone that is released from bone and targeted in the kidneys; deletion of the Dmp1 gene leads to a dramatic increase of FGF23 mRNA in osteocytes [7].…”