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CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

Dentin Matrix Protein 1 (DMP1): New and Important Roles for Biomineralization and Phosphate Homeostasis

C. Qin, R. D’Souza and J.Q. Feng*

Department of Biomedical Sciences, Texas A&M Health Science Center, Baylor College of Dentistry, 3302 Gaston Avenue, Dallas, TX 75246, USA

Correspondence: * corresponding author, jfeng{at}bcd.tamhsc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 GENE STRUCTURE AND REGULATION
 PROTEIN STRUCTURE AND METABOLISM
 TISSUE/CELL EXPRESSION
 BIOLOGICAL FUNCTIONS OF DMP1
 SUMMARY AND FUTURE RESEARCH
 REFERENCES
 
Previously, non-collagenous matrix proteins, such as DMP1, were viewed with little biological interest. The last decade of research has increased our understanding of DMP1, as it is now widely recognized that this protein is expressed in non-mineralized tissues, as well as in cancerous lesions. Protein chemistry studies have shown that the full length of DMP1, as a precursor, is cleaved into two distinct forms: the C-terminal and N-terminal fragments. Functional studies have demonstrated that DMP1 is essential in the maturation of odontoblasts and osteoblasts, as well as in mineralization via local and systemic mechanisms. The identification of DMP1 mutations in humans has led to the discovery of a novel disease: autosomal-recessive hypophosphatemic rickets. Furthermore, the regulation of phosphate homeostasis by DMP1 through FGF23, a newly identified hormone that is released from bone and targeted in the kidneys, sets a new direction for research that associates biomineralization with phosphate regulation.

Key Words: dentin matrix protein 1 • SIBLING family • dentinogenesis • osteogenesis • phosphate homeostasis • hypophosphatemic rickets


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
GENE STRUCTURE AND REGULATION
 PROTEIN STRUCTURE AND METABOLISM
 TISSUE/CELL EXPRESSION
 BIOLOGICAL FUNCTIONS OF DMP1
 SUMMARY AND FUTURE RESEARCH
 REFERENCES
 
Bone and dentin are mineralized tissues that develop through similar mechanisms and closely resemble each other in composition. During the formation of bone and dentin, osteoblasts and odontoblasts secrete unmineralized, type I collagen-rich matrices termed "osteoid" and "predentin", respectively. As precursors of bone and dentin, the organic phases of osteoid and predentin lie between the mineralization front and the cells; each is transformed to the mineralized phase with the deposition of hydroxyapatite crystals. This biomineralization process involves mechanisms that control the site and rate of apatite formation. For example, a rather uniform layer of osteoid and predentin is maintained under normal conditions of growth, indicating that the rate of formation of the unmineralized precursor layer is equal to the rate of mineralization. In contrast, in pathological conditions such as osteomalacia and dentinogenesis imperfecta, a disturbance in the controlling mechanisms results in aberrant widening of the osteoid seam and/or the predentin layer.

In addition to type I collagen, the extracellular matrix (ECM) of bone and dentin contains numerous non-collagenous proteins (NCPs). These NCPs are believed to actively promote and control the mineralization of collagen fibers and crystal growth within osteoid and predentin, when these tissues are converted to bone and dentin. DMP1 was identified by cDNA cloning (George et al., 1993) and is a prominent member of one category of NCPs, termed the SIBLINGs (Small Integrin-Binding Ligand, N-linked Glycoprotein) family. This family also includes bone sialoprotein (BSP), osteopontin (OPN), enamelin, matrix extracellular phosphoglycoprotein (MEPE), and dentin sialophosphoprotein (DSPP), in addition to DMP1 (Fisher et al., 2001; Fisher and Fedarko, 2003). DMP1 is expressed in bone (D’Souza et al., 1997; Hirst et al., 1997; MacDougall et al., 1998) as well as in dentin, and in non-mineralized tissues such as the brain, kidney, pancreas, and salivary and eccrine sweat glands (Ogbureke and Fisher, 2004, 2005, 2007; Terasawa et al., 2004). The amino acid sequence of DMP1 contains an unusually large number of acidic domains, a property that implicates it as a possible participant in regulating mineralization. This hypothesis is supported by both in vitro observations with MC3T3-E1 cells overexpressing DMP1 (Narayanan et al., 2001) and in vivo findings from Dmp1 knockout mice (Ye et al., 2004, 2005; Ling et al., 2005). More recent studies have identified DMP1 mutations as the cause of a novel disorder in humans, autosomal-recessive hypophosphatemic rickets (ARHR) (Feng et al., 2006; Lorenz-Depiereux et al., 2006).

The overall objectives of this review are to summarize the remarkable progress made in the last decade toward our understanding of the role of DMP1 in gene regulation, protein structure and metabolism, tissue/cell expression patterns, and biological functions in dentinogenesis, osteogenesis, and phosphate ion (Pi) homeostasis. We will conclude by providing an outlook for future research directions and the impact of new knowledge on the development of therapeutic interventions.


   GENE STRUCTURE AND REGULATION
TOP
 ABSTRACT
 INTRODUCTION
 GENE STRUCTURE AND REGULATION
PROTEIN STRUCTURE AND METABOLISM
 TISSUE/CELL EXPRESSION
 BIOLOGICAL FUNCTIONS OF DMP1
 SUMMARY AND FUTURE RESEARCH
 REFERENCES
 
The DMP1 gene has been mapped to 4q21 in humans, and to 5q21 in mice, where other SIBLING family members are clustered (Hirst et al., 1997; Fisher et al., 2001). DNA sequence data obtained from crocodiles (Toyosawa et al., 1999), chickens (Toyosawa et al., 2000), humans (Hirst et al., 1997; Fisher et al., 2001), mice (MacDougall et al., 1998), rats (Thotakura et al., 2000), and pigs (Kim et al., 2006) show that DMP1 cDNA is encoded by 6 exons with the following common features: (1) The first 5 exons are relatively small, ranging in size from 33 to 104 base pairs, and exon 6 is the largest, with 80% of the coding information; (2) exon 2 encodes the amino acids for the signal peptide; (3) exon 5 (45 bp) is spliced in some species (see below); and (4) intron 1 is the largest (3791 kb to ~ 6 kb) and is required for tissue specificity of DMP1 expression (Lu et al., 2005, 2007a), while intron 4 is the smallest (162–189 base pairs).

There are two Dmp1 transcripts: one with all exons, and one missing exon 5. In mice, the full-length transcript is the dominant form (MacDougall et al., 1998), whereas in humans, the one without exon 5 is the most abundant (personal communication with Ken White, University of Indiana). Currently, the biological significance of this variation among species is unknown.

DMP1 is predominantly expressed in bone and dentin (see below), suggesting that the transcription of DMP1 is highly regulated. It appears that there are two promoter control domains: a proximal one, located between the –2.4 kb and the +4 kb region, and a distal one, between the –2.4 kb and –9.6 kb regions. The proximal domain controls the early stage of Dmp1 expression, and the distal domain controls later expression (Lu et al., 2005). A similar finding is observed in osteogenesis (Feng et al., unpublished data). Moreover, Dmp1 is highly expressed in osteoblasts during embryonic development, but is mainly expressed in osteocytes during postnatal development (Fig. 1Go). These findings suggest that the transcriptional factors that control Dmp1 promoter activity may act in a stage-specific manner.


Figure 1
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  		Figure 1. DMP1 is highly expressed in mineralized tissues. (a) A whole-mount X-gal stain of an E15.5 Dmp1-lacZ knock-in embryo (left panel) and the insert (right panel), with an enlargement of the area outlined in the left panel re-stained with x-gal, show high lacZ expression in osteoblasts. Note that a lacZ reporter gene was used to replace exon 6 of the Dmp1 gene. The expression of lacZ, as demonstrated by X-gal staining, reflects endogenous Dmp1 expression. (b) A whole-mount X-gal stain of a skeleton from an 8-day-old Dmp1-lacZ knock-in pup with lacZ expressed in osteocytes (the enlarged insert). (c) DMP1 immunostain of bone matrix surrounding osteocytes (signal in brown). Both assays suggest that DMP1 is mainly expressed in the osteoblasts during embryonic development, and that this matrix protein is predominantly expressed in the osteocytes during postnatal development. (d) Summary of Dmp1-lacZ expression profiles in all hard tissues. Part of this Fig. is adapted from Feng et al.(2003).

 
AP-1, JunB, Runx2, Msx 1/2, Tcf/Lef, C/EBP, and YY-1 are transcription factors essential for bone and tooth tissue-specific regulation (Franceschi, 1999; Karsenty et al., 1999). Potential response elements for these transcriptional factors are present in DMP1 promoter sequences (Narayanan et al., 2002; Chen et al., 2004). The members of the AP-1 family, c-Jun and c-Fos, are likely involved in the transcriptional regulation of the DMP1 gene during early osteoblast differentiation, while they are not required for later stages of osteoblast differentiation (Narayanan et al., 2002). There are three potential response elements for Runx2 in the Dmp1 promoter; Dmp1 mRNA is completely absent in Runx2-null bone, but remains in the Runx2-null odontoblast layer. This work suggests that Runx2 may have different regulatory roles in DMP1 expression in osteogenesis and odontogenesis (Feng et al., 2002).

Using quantitative real-time RT-PCR assay, Foster and his colleagues recently showed that DMP1 is regulated by Pi in cementoblast cell lines (Foster et al., 2006). The time-course experiments showed that the strongest Dmp1 response to Pi occurred within 6–24 hrs. At a dosage of 5 mM P(i), the Dmp1 level was increased 30-fold over the control, along with a threefold increase of osteopontin, and down-regulation of bone sialoprotein (25% of control), osteocalcin (85% of control), and type I collagen (50% of control). These findings provide critical information on the DMP1 regulation of Pi homeostasis (see below).


   PROTEIN STRUCTURE AND METABOLISM
TOP
 ABSTRACT
 INTRODUCTION
 GENE STRUCTURE AND REGULATION
 PROTEIN STRUCTURE AND METABOLISM
TISSUE/CELL EXPRESSION
 BIOLOGICAL FUNCTIONS OF DMP1
 SUMMARY AND FUTURE RESEARCH
 REFERENCES
 
DMP1 contains an unusually large number of acidic domains that are rich in Ser, Glu, and Asp; many of the Ser are in the consensus motif for potential phosphorylation by casein kinases I and II. Data obtained from protein chemistry studies on DMP1 isolated from rat bone showed that, on average, a full-length DMP1 molecule should contain 53 phosphate groups attached to the protein (Qin et al., 2003). The acidic nature of DMP1 indicates potentially high calcium ion-binding capacity, a property considered necessary for a protein to participate in mineralization.

There are three highly conserved regions spanning residues 67–83, 157–184, and 449–473 in rat DMP1 (Qin et al., 2006). The first region, containing a Ser at position 74 that links a glycosaminoglycan (GAG) chain to the protein, is named "GAG-domain". The second region, spanning Val157-Gly184 of rat DMP1 that contains a primary cleavage site [i.e., NH2-terminal peptide bond of Asp 181 (Qin et al., 2003)], is designated as a cleavage domain. The third region, corresponding to Arg449-Tye473 of rat DMP1, is the C-terminal domain, which has been shown to be important for the functions of DMP1, since deletion mutations in this region lead to ARHR in humans (Feng et al., 2006).

Although several Dmp1 cDNA species have been cloned and sequenced, the expected full-length DMP1 protein has not been reported. Instead, the 37-kDa N-terminal and 57-kDa C-terminal fragments were isolated from the ECM of bone and dentin, respectively (Qin et al., 2003). Phosphate analysis showed that the C-terminal fragment contains 41 phosphate groups, while the N-terminal fragment possesses only 12 phosphate groups. The RGD tripeptide is located in the central region of the 57-kDa C-terminal. Extensive sequencing of tryptic peptides derived from DMP1 fragments, along with comparison with the cDNA-deduced sequence, has confirmed that rat DMP1 is proteolytically cleaved at 4 bonds, Phe173-Asp174, Ser180-Asp181, Ser217-Asp218, and Gln221-Asp222. Among these, Ser180-Asp181 is a key cleavage site (Qin et al., 2003). This study suggests that the full-length DMP1 is likely a precursor, and the 37-kDa and the 57-kDa fragments are its functional forms (Qin et al., 2004).

The uniformity of cleavages at the N-terminal peptide bonds of aspartyl residues (i.e., at X-Asp bonds) indicates that a single group proteinase may be involved. One group of candidate enzyme(s) responsible for DMP1 processing is bone morphogenetic protein 1 (BMP-1)/tolloid-like metalloproteinase (Steiglitz et al., 2004). However, these enzymes are widely expressed in mesenchymal-derived tissues and have been shown to cleave several other protein precursors, including those of several collagens (types I, II, III, V, VII, VI), biglycan, and lysyl oxidase at selected X-Asp bonds, suggesting that the enzymes for the cleavage of DMP1 may not be tissue-specific.

More recent studies have shown that some of the N-terminal fragments of DMP1 in bone and dentin ECM exist as a proteoglycan form referred to as "DMP1-PG" (Qin et al., 2006). This proteoglycan contains a single glycosaminoglycan (GAG) chain made predominantly of chondroitin-4-sulfate and linked to the core protein via Ser74, located in the Ser74-Gly75 dipeptide. Amino acid sequence alignment analysis showed that the Ser74-Gly75 dipeptide and its flanking regions are highly conserved among a wide range of species, from caiman to Homo sapiens (Qin et al., 2006). Such a high level of conservation suggests that the GAG form may have biological significance.

Based on the information described above, it is clear that (a) the full-length form of DMP1 very likely represents a precursor form; (b) the processed fragments are the functional forms; and (c) the enzyme(s) for DMP1 cleavage is not tissue-specific. Interestingly, DSPP, another SIBLING member, is also synthesized as a precursor and is cleaved into dentin sialoprotein (DSP, N-terminal) and dentin phosphoprotein (DPP, C-terminal) (Feng et al., 1998).


   TISSUE/CELL EXPRESSION
TOP
 ABSTRACT
 INTRODUCTION
 GENE STRUCTURE AND REGULATION
 PROTEIN STRUCTURE AND METABOLISM
 TISSUE/CELL EXPRESSION
BIOLOGICAL FUNCTIONS OF DMP1
 SUMMARY AND FUTURE RESEARCH
 REFERENCES
 
DMP1 was originally isolated from rat dentin and was thought to be specific for dentin only (George et al., 1993). Later, several research groups demonstrated the expression of DMP1 in bone (D’Souza et al., 1997; Hirst et al., 1997; MacDougall et al., 1997; Feng et al., 2002) at a much higher level than in dentin (Fig. 1Go) (Toyosawa et al., 2001; Butler et al., 2002; Feng et al., 2002; Qin et al., 2003). More recently, DMP1 has been observed in several non-mineralized tissues, such as the brain, salivary glands, and certain tumors of epithelial origin (Fisher et al., 2004; Terasawa et al. 2004; Ogbureke and Fisher, 2004, 2005, 2007; Ogbureke et al., 2007).

In teeth, DMP1 is expressed in the dental pulp cells, odontoblasts, predentin, dentin, and cementum (Fig. 1dGo). In dentin, it is predominantly localized in the peritubular region and is co-localized with DSP, a processed NH2-terminal product of DSPP (Baba et al., 2004). In cementum, DMP1 is mainly present in cementocytes and the matrix surrounding cementocyte processes (Feng et al., 2003; Baba et al., 2004).

In the skeleton, DMP1 mRNA is highly expressed in the primary hypertrophic chondrocytes and osteoblasts during embryonic development, whereas this protein is primarily expressed in the osteocytes during postnatal development (Toyosawa et al., 2001; Feng et al., 2002) (Figs. 1b, 1cGo).

In the soft tissues, DMP1 is widely distributed throughout the gray matter of the cerebrum and brainstem. It has been identified on the cell surfaces of the large pyramidal cells, Purkinje cells, ependymal cells, subependymal cells, and choroids plexus (Terasawa et al., 2004). In the pancreas, DMP1 is observed in the Langerhans islets (Terasawa et al., 2004). In the kidney, it is found in the epithelium of the distal tubule and the Henle’s loop (Terasawa et al., 2004; Ogbureke and Fisher, 2005). In the salivary glands and the eccrine sweat glands, DMP1 is present in the duct cells and is co-localized with matrix metalloproteinase-9 (MMP-9), a binding partner of DMP1 (Ogbureke and Fisher, 2004, 2007).

In cancer tissues, DMP1 is detected in the breast, uterus, colon, lung, and oral cavity (Chaplet et al., 2003; Toyosawa et al., 2004; Ogbureke et al., 2007). In lung and oral cancers, DMP1 is co-localized with MMP-9. Additionally, DMP1 has been shown to facilitate the invasion of colon cancer cells by bridging MMP-9 to integrin and CD44 (Toyosawa et al., 2004; Karadag et al., 2005; Ogbureke et al., 2007).


   BIOLOGICAL FUNCTIONS OF DMP1
TOP
 ABSTRACT
 INTRODUCTION
 GENE STRUCTURE AND REGULATION
 PROTEIN STRUCTURE AND METABOLISM
 TISSUE/CELL EXPRESSION
 BIOLOGICAL FUNCTIONS OF DMP1
SUMMARY AND FUTURE RESEARCH
 REFERENCES
 
As stated above, the expression of DMP1 is much broader than previously thought, indicating that this protein may have multiple biological functions. However, this review focuses only on the roles of DMP1 in odontogenesis, osteogenesis, and Pi homeostasis. Potential roles of DMP1 in non-mineralized tissues can be found in several relevant references (Fisher et al., 2004; Ogbureke and Fisher, 2004, 2005, 2007; Terasawa et al., 2004; Ogbureke et al., 2007).

DMP1 Promotes Hydroxyapatite Formation and Controls Cell Differentiation in vitro
The first evidence showing the participation of DMP1 in biomineralization came from transfection experiments. MC3T3-E1 cells overexpressing DMP1 demonstrated accelerated differentiation and the earlier onset of mineralization (Narayanan et al., 2001). Subsequently, Feng and colleagues reported that the expression of DMP1 was closely associated with "bone nodule" formation and mineralization in primary rat calvarial cell cultures (Feng et al., 2002).

He and colleagues reported that specific acidic clusters in DMP1 may provide the molecular design necessary for controlling the formation of oriented calcium phosphate crystals, and that the self-assembly of acidic clusters into a beta-sheet template of DMP1 is likely required for its role in biomineral induction (He et al., 2003a,b). Interestingly, Tartaix and colleagues showed that the non-phosphorylated form of DMP1 made from prokaryotes acts as a hydroxyapatite nucleator, whereas the phosphorylated form had no apparent effect on hydroxyapatite formation and growth (Tartaix et al., 2004). Studies show that the effects of DMP1 derived from eukaryotes are more complicated: The full-length bovine DMP1 made by human bone marrow stromal cells is a potent inhibitor of mineralization, whereas the DMP1-C-terminal (57 kDa) fragment isolated from rat bone is a hydroxyapatite nucleator. More recently, Gajjeraman et al. showed that both full-length recombinant DMP1 and native DMP1 C-terminal fragments isolated from rat bone accelerated the nucleation of hydroxyapatite in the presence of type I collagen, whereas the N-terminal domain of DMP1 (amino acid residues 1–334) inhibited hydroxyapatite nucleation (Gajjeraman et al., 2007).

Earlier in vitro studies showed that DMP1 promotes cell attachment through the RGD motif in a cell- and tissue-specific manner (Kulkarni et al., 2000), suggesting a possible interaction of this protein with specific cells and activating signaling pathways. This speculation is strengthened by the observation that exogenous DMP1 added to exposed dental pulp could act as a morphogen trigger and/or promoter of the differentiation of undifferentiated ectomesenchymal cells in the pulp toward the odontoblast lineage (Narayanan et al., 2006). Furthermore, it was reported that DMP1 is primarily localized in the nuclear compartment of undifferentiated osteoblasts, implying that DMP1 could act as a transcriptional component for the activation of osteoblast/odontoblast-specific genes, like osteocalcin (Narayanan et al., 2003).

Taken together, the in vitro studies suggest that DMP1 (most likely its C-terminal fragment) acts as a hydroxyapatite nucleator and also controls cell differentiation through targeting the nucleus and/or interacting with cell-surface integrin/CD44 receptors.

DMP1 Controls Osteogenesis in vivo
DMP1 is highly expressed in osteoblasts during embryonic development (Fig. 1aGo). If it is essential for cell differentiation and mineralization, as suggested by in vitro studies, it might be expected that Dmp1 knock-out mice would show little or no mineral in their bones. However, Dmp1-null newborns display no gross abnormalities, indicating that there must be redundant genes that compensate for DMP1 function during early development (Feng et al., 2003).

During postnatal development, Dmp1-null pups develop abnormalities, which are typically rickets (delayed secondary ossification, enlarged growth plate with dramatic expansion of hypertrophic chondrocyte zone, and short limbs) and osteomalacia (defects in mineralization), starting during the first week after birth and worsening with age (Ling et al., 2005; Ye et al., 2005; Feng et al., 2006). All these defects appear linked to DMP1 functions in the osteocytes (Fig. 2Go), cells that account for more than 95% of bone cells and are essential for mechanosensation and transduction (Bonewald, 2006). The following evidence seems to agree with this hypothesis:


Figure 2
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  		Figure 2. DMP1 controls osteogenesis and dentinogenesis. (a) Resin-embedded alveolar bone (3-month-old) was acid-etched to remove mineral, leaving behind the plastic for visualization of the osteocyte lacuno-canalicular system by scanning electron microscopy (SEM). (b) SEM images of a fractured 1st molar (upper panel, 3-month-old), and resin-cast dentin tubules (lower panel, dentin tubules filled with resin), showing the normal structure of dentin. (c) The current working hypothesis: DMP1 is required for both osteogenesis and odontogenesis by controlling cell differentiation and maturation, as well as mineralization. The deletion of DMP1 results in defects in both processes. Part of the Figure is adapted from Ye et al.(2004) and Feng et al.(2006).

 
  1. DMP1 is expressed in all tissues that undergo mineralization, but its expression in osteocytes is much higher than in any other cell types, as determined by in situ hybridization, lac Z knock-in expression, and immunostaining (Feng et al., 2002, 2003, 2006).
  2. Through immunostaining, DMP1 appears to be highly abundant in the dendritic processes of osteocytes (Figs. 1b, 1cGo). Through the immuno-gold assay, it appears to be localized on the canalicular walls along the lamina limitans (M. McKee at McGill University, personal communication).
  3. A dramatic increase in Dmp1 expression is observed in osteocytes in response to mechanical loading (Gluhak-Heinrich et al., 2003; Yang et al., 2004, 2005).
  4. Dmp1 null mice show major abnormalities in osteocyte morphology (Feng et al., 2006).
  5. Mechanical loading of the ulna from Dmp1 null mice produces strains 1.7 times higher than the strains in the controls, indicating a significant change in the elasticity and/or stiffness properties of the bones (Rios et al., 2005).
  6. One of the striking observations in Dmp1 null mice is the progressive change in the skeletal properties with aging, such as bony protrusions formed over time, which appear primarily at sites of muscle insertion (Ye et al., 2005).

All of these observations appear to be associated with a defect in the maturation of osteoblasts into osteocytes (Feng et al., 2006).

The roles of DMP1 in mineralization during postnatal development are also linked to osteocytes (Figs. 2Go, 3Go). This concept goes against current dogma, since osteoblasts, not osteocytes, were thought to be critical for mineralization. The key evidence in support of this hypothesis is:


Figure 3
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  		Figure 3. Mice lacking DMP1 display defects in mineralization. (a) TEM images of 3-month-old tibias showing that the mineral matrix (black) surrounding the control osteocyte is smooth (left panel), and that spherical structures of calculo-spherulites were present in Dmp1-KO mice, with markedly reduced propagation into the surrounding osteoid (right panel, arrow). (b) Images of back-scattered SEMs of tibias (samples were treated with osmium to preserve cell morphology) show poor mineral matrix (white) surrounding KO osteocytes (right). *(c) Confocal microscopy images of fluorochrome labeling, counterstained with DAPI for visualization of osteocyte nuclei (blue). The Dmp1-KO osteocytes are buried in diffuse fluorochrome label, suggesting a defect in the process of mineral propagation (right panel). (d) H&E-stained sections of molars show an extended predentin (red layer in newly formed dentin matrix) and reduced dentin in Dmp1 null mice (KO), compared with the control (Cont) mice. (e) Back-scattered SEM images reveal a dramatic decrease in mineral (white color), plus a striking change in dentin matrix structure (right panel) compared with the control mice. The data are adapted from Ye et al.(2004) and Feng et al.(2006).

 
  1. A combination of the injection of calcein/Alizarin Red in conjunction with DAPI nuclear counterstaining (an assay allowing for visualization of the mineralization front and its relationship with the osteocytes) shows three discrete lines of fluorochrome labeling in the controls, which are clearly separated from the osteocytes (Feng et al., 2006) (Fig. 3aGo, left), whereas in Dmp1 KO mice, the labeling of exposed sites of hydroxyapatite occurred in numerous dispersed, punctate areas surrounding the osteocyte nuclei, which is reminiscent of a diffuse, osteomalacic form of mineralization (Fig. 3aGo, right).
  2. Back-scattered SEM showed mineral to be evenly distributed surrounding the osteocyte lacunae in the control bone (Fig. 3bGo, left, white); however, the mineral content was either absent or sparsely located in regions surrounding Dmp1-null osteocytes (Fig. 3bGo, right).
  3. The scanning transmission electron microscopy (STEM) images showed that the mineralized matrix surrounding the osteocytes is evenly distributed (Figs. 3c-3eGo, left). In contrast, spherical structures in the Dmp1-null mice, reminiscent of calculo-spherulites, are present, with markedly reduced propagation into the surrounding osteoid (Fig. 3cGo, right, black).

DMP1 Controls Dentinogenesis in vivo
DMP1 is expressed in both pulp and odontoblast cells (Feng et al., 2003), and deletion of the Dmp1 gene leads to defects in odontogenesis and mineralization (Ye et al., 2004; Lu et al., 2007b) (Figs. 2Go, 3Go). The phenotype includes a partial failure of maturation of predentin into dentin, enlarged pulp chambers, increased width of the predentin zone with a reduced dentin wall, hypomineralization, a three-fold reduction in dentin appositional rate, and abnormalities in the dentinal tubule system. Furthermore, the tooth phenotype of these mice is similar to that in dentin sialophosphoprotein (Dspp)-null mice (Sreenath et al., 2003), suggesting that both DMP1 and DSPP may participate in the same signaling pathway. However, Dmp1-null mice displayed delayed development of the third molar, although there has been no such report in Dspp-null mice.

Mechanistic studies showed that there is a dramatic reduction of DSPP in Dmp1-null mice (Ye et al., 2005). This information is in agreement with the reports from in vitro studies where DMP1-response elements in the Dspp gene have been identified (Narayanan et al., 2006). The re-expression of Dmp1 under the control of the Col1a1 promoter, which is active during the entire odontogenic process, rescued the defects of mineralization as well as the defects in the dentinal tubules and third molar development. In contrast, the re-expression of DMP1 in mature odontoblasts driven by the Dspp promoter produced only a partial rescue of the mineralization defects. In addition, the expression of osterix in Dmp1-null pulp/odontoblast cells was sharply reduced, and the transgenic re-expression of DMP1 completely rescued the osterix expression in these null cells. Analysis of these data suggests that DMP1 is a key regulator of odontoblast differentiation, the formation of the dentin tubular system and mineralization, and that DMP1 expression is required in both early and late odontoblasts for normal odontogenesis to proceed (Fig. 2cGo) (Lu et al., 2007b). Interestingly, heterozygous Dmp1-null mice or Dmp1-overexpressing mice display no gross abnormalities, suggesting that there may be a threshold level of DMP1 required for normal odontogenesis and osteogenesis, but above that level, the actual amount of DMP1 does not have a dose-related effect (Ye et al., 2004; Lu et al., 2007b).

DMP1 Controls Pi Homeostasis through FGF23 in vivo
The most unexpected phenotype in Dmp1 null mice is hypophosphatemia (Ye et al., 2005; Feng et al., 2006). This finding leads to a new concept that a non-collagenous matrix protein regulates Pi homeostasis, and to the discovery of DMP1 mutations in autosomal-recessive hypophosphatemia rickets (ARHR) (Feng et al., 2006; Lorenz-Depiereux et al., 2006).

It is well-known that the kidneys control the Pi balance through parathyroid hormone and 1, 25 (OH)2 vitamin D3, and that bone is viewed as the key target organ, due to its "Pi reservoir". The recent discovery of fibroblast growth factor 23 (FGF23), a hormone secreted from osteoblasts/osteocytes and targeted in the kidneys, extends the function of bone to an endocrine organ in the regulation of Pi homeostasis (Schiavi, 2006; Liu et al., 2007).

FGF23 is mainly expressed in the wild-type osteoblasts, and the deletion of Dmp1 leads to a dramatic increase of FGF23 mRNA in the osteocytes (Feng et al., 2006). Apparently, this sharp increase is likely due to defects in the maturation of osteoblasts into osteocytes by unknown mechanisms (Fig. 4aGo). The key pathological consequence due to the reduction of serum Pi in Dmp1 null mice is rickets, a short stature due to malformed epiphyses and growth plates. Initially, it was thought that DMP1 has a direct function in the hypertrophic chondrocytes, because of its expression in these cells (Ye et al., 2005). Now it is clear that low Pi leads to a slowdown in apoptosis in the hypertrophic chondrocytes, and a delay in blood vessel invasion for secondary ossification (Fig. 4bGo) (Ye et al., 2005). The most convincing data in support of this conclusion are that a diet high in Pi fully rescued Dmp1 null rickets, but not osteomalacia (Feng et al., 2006).


Figure 4
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  		Figure 4. DMP1 controls Pi homeostasis through FGF23. (a) In situ hybridization shows a sharp increase in FGF23 mRNA (red) from 10-day-old Dmp1-KO osteocytes obtained from jaws (upper panel, control; lower panel, KO). The data are adapted from Feng et al.(2006). (b) Summary of defects of Pi homeostasis in Dmp1-KO mice. Note that FGF23 is mainly released from normal osteoblasts, which targets kidneys for inhibition of Pi re-absorption. In pathological conditions such as mutations of DMP1 or deletion of Dmp1, overproduction of FGF23 in bone leads to hypophosphatemia rickets, including defects in the epiphyses and growth plate.

 

   SUMMARY AND FUTURE RESEARCH
TOP
 ABSTRACT
 INTRODUCTION
 GENE STRUCTURE AND REGULATION
 PROTEIN STRUCTURE AND METABOLISM
 TISSUE/CELL EXPRESSION
 BIOLOGICAL FUNCTIONS OF DMP1
 SUMMARY AND FUTURE RESEARCH
REFERENCES
 
Since the initial discovery of DMP1, much information has been obtained with regard to its gene regulation, biochemical characteristics, and cell/tissue localizations and functions: First, mechanical loading and Pi level are two key factors controlling DMP1 levels. Second, the full-length DMP1 acts as a precursor, and the 57-kDa C-terminal fragment is likely to be a key functional form. Third, DMP1 is critical for the control of mineral propagation instead of initiation. Fourth, because DMP1 controls the maturation of both odontoblasts and osteoblasts, defects in this process will lead to changes in the morphologies of dentin (such as dentin tubules) and bone (especially the osteocyte-canalicular system). Finally, an increase in the FGF23 production in the Dmp1 null osteocytes is the key pathological factor responsible for hypophosphatemic rickets. Considered together, the loss- and gain-function animal models and identification of DMP1 mutations in ARHR patients strongly support the notion that DMP1 is a new key player in the control of mineralization and Pi homeostasis.

Yet, many fundamental questions remain: How does DMP1 control Pi homeostasis in the normal physiological condition? Does DMP1 directly regulate FGF23? How does DMP1 control intracellular functions (at the nucleus level and/or through MAP kinase signaling)? Do receptors for DMP1 exist? What is the three-dimensional structure of DMP1? How is DMP1 processed? What is the function of each individual fragment (such as the C-terminal or N-terminal)? Does DMP1 and/or its processed fragments form protein-protein complexes with other molecules? What are the roles of DMP1 in non-mineralized tissues such as the brain, where it is broadly expressed? Importantly, do SIBLING proteins talk to each other? For example, MEPE has been shown to inhibit mineralization and regulate Pi homeostasis (Bresler et al., 2004; Rowe, 2004; Rowe et al., 2004, 2005, 2006), and Dmp1 null mice display high levels of MEPE in vivo (Feng et al., unpublished data). The relationship between DMP1 and MEPE in vivo needs to be clarified.

Furthermore, nestin (About et al., 2000; Oka et al., 2007) and heat-shock protein (HSP)-25 (Nakasone et al., 2006) have been shown to be good phenotypic markers of secretory odontoblasts. The application of these useful markers plus DSPP will greatly facilitate the studies of the roles of DMP1 during tooth development and pathological conditions.

Finally, we believe that the outcomes of these studies will shed new light on the manner in which DMP1 controls osteogenesis and dentinogenesis in both healthy individuals and those with disease.

Received for publication August 22, 2007. Revision received October 1, 2007. Accepted for publication October 1, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 GENE STRUCTURE AND REGULATION
 PROTEIN STRUCTURE AND METABOLISM
 TISSUE/CELL EXPRESSION
 BIOLOGICAL FUNCTIONS OF DMP1
 SUMMARY AND FUTURE RESEARCH
 REFERENCES
 

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Journal of Dental Research, Vol. 86, No. 12, 1134-1141 (2007)
DOI: 10.1177/154405910708601202
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