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 DOI: 10.1177/154405910708601202

2007 86: 1134J DENT RESC. Qin, R. D'Souza and J.Q. Feng

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

  

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INTRODUCTION

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 vitroobservations 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

ABSTRACTPreviously, 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.

Received August 22, 2007; Last revision October 1, 2007; Accepted

October 1, 2007

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 ScienceCenter, Baylor College of Dentistry, 3302 Gaston Avenue, Dallas, TX75246, USA; *corresponding author, jfeng@bcd.tamhsc.edu

J Dent Res 86(12):1134-1141, 2007

CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

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J Dent Res 86(12) 2007 DMP1 in Mineralization and Pi Homeostasis 1135

future research directions and the impact of new knowledge on

the development of therapeutic interventions.

GENE STRUCTURE AND REGULATIONThe 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 Dmp1expression, 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 post-natal development

(Fig. 1). These findings suggest that the transcriptional factors

that control Dmp1 promoter activity may act in a stage-specific

manner.

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 etal., 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 Dmp1level was increased 30-fold over the control, along with a three-

fold increase of osteopontin, and down-regulation of bone

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 inthe left panel re-stained with x-gal, show high lacZ expression inosteoblasts. Note that a lacZ reporter gene was used to replace exon 6of the Dmp1 gene. The expression of lacZ, as demonstrated by X-galstaining, reflects endogenous Dmp1 expression. (b) A whole-mount X-gal stain of a skeleton from an 8-day-old Dmp1-lacZ knock-in pup withlacZ expressed in osteocytes ( the enlarged insert). (c) DMP1immunostain of bone matrix surrounding osteocytes (signal in brown).Both assays suggest that DMP1 is mainly expressed in the osteoblastsduring embryonic development, and that this matrix protein ispredominantly expressed in the osteocytes during post-nataldevelopment. (d) Summary of Dmp1-lacZ expression profiles in all hardtissues. Part of this Fig. is adapted from Feng et al. (2003).

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International and American Associations for Dental Research

1136 Qin et al. J Dent Res 86(12) 2007

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 METABOLISMDMP1 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.,NH

2-terminal peptide bond of Asp181 (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 EXPRESSIONDMP1 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 etal., 1997; Feng et al., 2002) at a much higher level than in

dentin (Fig. 1) (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. 1d). 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 post-natal development

(Toyosawa et al., 2001; Feng et al., 2002) (Figs. 1b, 1c).

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 etal., 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).

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J Dent Res 86(12) 2007 DMP1 in Mineralization and Pi Homeostasis 1137

BIOLOGICAL FUNCTIONS OF DMP1As 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 etal., 2004; Ogbureke and Fisher, 2004, 2005, 2007; Terasawa etal., 2004; Ogbureke et al., 2007).

DMP1 Promotes Hydroxyapatite Formation and Controls Cell Differentiation in vitroThe 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 vivoDMP1 is highly expressed in osteoblasts during embryonic

development (Fig. 1a). 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 post-natal 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. 2), cells that

Figure 2. DMP1 controls osteogenesis and dentinogenesis. (a) Resin-embedded alveolar bone (3-month-old) was acid-etched to removemineral, leaving behind the plastic for visualization of the osteocytelacuno-canalicular system by scanning electron microscopy (SEM). (b)SEM images of a fractured 1st molar (upper panel, 3-month-old), andresin-cast dentin tubules (lower panel, dentin tubules filled with resin),showing the normal structure of dentin. (c) The current workinghypothesis: DMP1 is required for both osteogenesis and odontogenesisby controll ing cell differentiation and maturation, as well asmineralization. The deletion of DMP1 results in defects in bothprocesses. Part of the Figure is adapted from Ye et al. (2004) and Fenget al. (2006).

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International and American Associations for Dental Research

1138 Qin et al. J Dent Res 86(12) 2007

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:

(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 insitu 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, 1c). 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 post-natal

development are also linked to osteocytes (Figs. 2, 3). 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:

(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. 3a, 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. 3a, right).

(2) Back-scattered SEM showed mineral to be evenly

distributed surrounding the osteocyte lacunae in the

control bone (Fig. 3b, left, white); however, the mineral

content was either absent or sparsely located in regions

surrounding Dmp1-null osteocytes (Fig. 3b, right).

(3) The scanning transmission electron microscopy

(STEM) images showed that the mineralized matrix

surrounding the osteocytes is evenly distributed (Figs.

3c-3e, 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. 3c, right, black).

DMP1 Controls Dentinogenesis in vivoDMP1 is expressed in both pulp and odontoblast cells (Feng etal., 2003), and deletion of the Dmp1 gene leads to defects in

odontogenesis and mineralization (Ye et al., 2004; Lu et al.,2007b) (Figs. 2, 3). 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,

Figure 3. Mice lacking DMP1 display defects in mineralization. (a) TEMimages of 3-month-old tibias showing that the mineral matrix (black)surrounding the control osteocyte is smooth (left panel), and thatspherical structures of calculo-spherulites were present in Dmp1-KOmice, 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) showpoor mineral matrix (white) surrounding KO osteocytes (right). *(c)Confocal microscopy images of fluorochrome labeling, counterstainedwith DAPI for visualization of osteocyte nuclei (blue). The Dmp1-KOosteocytes are buried in diffuse fluorochrome label, suggesting a defectin the process of mineral propagation (right panel). (d) H&E-stainedsections of molars show an extended predentin (red layer in newlyformed dentin matrix) and reduced dentin in Dmp1 null mice (KO),compared with the control (Cont) mice. (e) Back-scattered SEM imagesreveal a dramatic decrease in mineral (white color), plus a strikingchange in dentin matrix structure (right panel) compared with thecontrol mice. The data are adapted from Ye et al. (2004) and Feng etal. (2006).

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J Dent Res 86(12) 2007 DMP1 in Mineralization and Pi Homeostasis 1139

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 etal., 2005). This information is in

agreement with the reports from invitro studies where DMP1-

response elements in the Dsppgene 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. 2c) (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 vivoThe 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. 4a). 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.

4b) (Ye et al., 2005). The most convincing data in support of

this conclusion are that a diet high in Pi fully rescued Dmp1

Figure 4. DMP1 controls Pi homeostasis through FGF23. (a) In situ hybridization shows a sharp increasein 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 Pihomeostasis in Dmp1-KO mice. Note that FGF23 is mainly released from normal osteoblasts, whichtargets kidneys for inhibition of Pi re-absorption. In pathological conditions such as mutations of DMP1 ordeletion of Dmp1, overproduction of FGF23 in bone leads to hypophosphatemia rickets, includingdefects in the epiphyses and growth plate.

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International and American Associations for Dental Research

1140 Qin et al. J Dent Res 86(12) 2007

null rickets, but not osteomalacia (Feng et al., 2006).

SUMMARY AND FUTURE RESEARCHSince 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.

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International and American Associations for Dental Research

94

RECRUITMENT

ERRATUM

In the December Table of Contents under “Critical Reviews in Oral

Biology & Medicine”, the description for the article “Dentin

Matrix Protein 1 (DMP1): New and Important Roles for

Biomineralization and Phosphate Homeostasis” [C. Qin, R.

D´Souza, and J.Q. Feng, J Dent Res 86(12):1134-1141, 2007] was

incorrect. It should have stated: “This review summarizes the

progress made in the last decade toward our understanding of

the role of DMP1 in gene regulation, protein structure and

NORTH CAROLINA – Department of Orthodontics - The School of Dentistry at the University

of North Carolina at Chapel Hill is recruiting for the Chair, Department of Orthodontics.

The University of TexasHealth Science Center at San Antonio Chair -Department of Oral & Maxillofacial SurgeryThe University of Texas Health Science Center at San Antonio (UTHSC-SA) invites applications for the position of Chair, Department of Oral &Maxillofacial Surgery, Dental School.

The Chair provides leadership in advancing educational programs;strengthening research contributions; developing models of patient care andeducation; interacting with communities, health professionals, hospitals,and schools; expanding financial resources; and increasing national andinternational prominence of the school.

Qualifications include a DDS/DMD degree, completion of an advancededucation program in Oral & Maxillofacial Surgery, certification by the American Board of Oral and Maxillofacial Surgery and eligibility forlicensure in Texas.

Nominations and applications should be directed to:Spencer Redding, DDS, M Ed Chair, Search Committee for Chair, Department of Oral & Maxillofacial SurgeryThe University of Texas Health Science Center at San Antonio Dental School7703 Floyd Curl Drive, MSC: 7919/San Antonio, Texas 7822-3900/Fax: 210-567-3334/Email: redding@uthscdsa.edu

Salary and benefits are competitive and reflect qualifications and experience.Applicants should supply a letter of interest, a summary of experiences thataddress the above qualifications, curriculum vitae, and names and contact information for four references. Permission to contact referencesshould be provided in the letter. The Search Committee will begin reviewingapplications immediately and will continue until the position is filled.

All faculty appointments are designated as security-sensitive positions. TheUniversity of Texas Health Science Center at San Antoniois an Equal Opportunity, Affirmative Action Employer.

metabolism, tissue/cell expression patterns, and biological

functions in dentinogenesis, osteogenesis, and phosphate ion

homeostasis, and provides an outlook for future research direc-

tions and the impact of new knowledge on the development of

therapeutic interventions.” The publisher regrets this error.

This full-time position is a tenured academic appointment at the level ofAssociate or Full Professor commensurate with the candidate’s qualifica-tions and experience. The Chair provides leadership and guidance for theDepartment of Orthodontics in achieving the School’s missions of edu-cation, research, patient care, and service. The department is responsiblefor the orthodontic curricula in both the pre-doctoral DDS and graduate-specialty programs. Applicants must have a DDS or DMD degree (orequivalent) and advanced specialty training in Orthodontics. Board certi-fication in orthodontics and a MS (or PhD) degree are preferred.Applicants must have had at least 5 years’ experience in dental educationor research, and proven leadership abilities. Competitive candidates will

have interests in an administrative career and a strong research back-ground in an orthodontic-related field of study. Participation in fundedresearch and/or the Orthodontic Dental Faculty Practice desired. SendCV and four references to Dr. Ron Strauss, Chair, Orthodontics ChairSearch Committee, UNC School of Dentistry, CB # 7450, Chapel Hill,NC, 27599-7450 or to: ron_strauss@unc.edu .

The University of North Carolina is an Equal Opportunity/Affirmative Action employer.

94

95

The Department of Orofacial Sciences, School ofDentistry, University of California, San Francisco seeksapplicants for a full-time faculty position as Assistant orAssociate Professor of Periodontology in the Clinicalseries, in the Division of Periodontology. Applicantsmust have a dental degree (DDS, DMD, or equivalent)and a certificate of advanced training in periodontology.Responsibilities will include didactic and clinical teach-ing in pre-doctoral and post-doctoral dental programs,patient care, and service. Experience in teaching, placement of dental implants, and conscious sedationtechniques is desired. Intramural practice opportunitiesare available. Salary and rank are commensurate withexperience. This position will remain open until filled,

but applications received by April 1, 2008 will receiveinitial consideration. UCSF seeks candidates whose expe-rience, teaching, research, or community service has pre-pared them to contribute to our commitment to diversi-ty and excellence. Interested applicants should submit aletter of interest, curriculum vitae and the names of fourreferences to: Dr. Gary Armitage, Committee Chair,University of California, San Francisco, Department ofOrofacial Sciences, Box 0650, San Francisco, California94143-0650.

The University is an Equal Opportunity/Affirmative ActionEmployer. All qualified applicants are encouraged to apply,including minorities and women.

The Faculty of Dentistry, University of Toronto invites applications for a full-timetenure-stream/tenured position in Dental Public Health within the multidiscipli-nary Division of Diagnostic and Biological Sciences. The appointment will be atthe rank of Associate or Full Professor, and will begin on July 1, 2008. TheDiscipline of Dental Public Health includes undergraduate, graduate, and special-ty training elements. It will be closely allied with the proposed new School of PublicHealth at the University of Toronto. A primary responsibility of the candidate willbe to develop an independent research program to complement existing research atthe Faculty of Dentistry and in collaboration with related departments in theUniversity. Other responsibilities will include acting as Director of the SpecialtyProgram in Dental Public Health, and involvement in undergraduate teaching andcontinuing education. Requirements: (i) an advanced research degree, preferably aPh D (or equivalent), and a record of high-quality research as a principal investiga-tor in Public Health Dentistry; (ii) experience in curriculum development for teach-ing Dental Public Health; (iii) expertise in the practice of Public Health Dentistry;and (iv) eligible for certification as a specialist in Dental Public Health in Ontario.Salary and rank will be commensurate with the candidate’s qualifications and expe-rience. Applicants should submit a detailed curriculum vitae and the names andcontact information of three references to: Dr. Grace Bradley, Associate Dean,Department of Diagnostic and Biological Sciences, Faculty of Dentistry, Universityof Toronto,124 Edward St., Toronto, Ontario M5G 1G6. Tel:416-979-4900 Ext.4416. E-mail:grace.bradley@dentistry.utoronto.ca. A response by February 15,2008, will be appreciated; however, applications may continue to be considereduntil the position is filled. The University of Toronto is strongly committed todiversity within its community and especially welcomes applications from visibleminority group members, women, Aboriginal persons, persons with disabilities,members of sexual minority groups, and others who may add to the diversity ofideas. All qualified candidates will be encouraged to apply; however, Canadian andpermanent residents will be given priority.

Associate/Full ProfessorDental Public Health, Faculty of Dentistry,

University of TorontoDeadline: February 15, 2008, or until filled

The UCLA School of Dentistry, Division of Oral Biology, invitesapplications for a full-time tenure-track position at the AssistantProfessor level (Tracking #1350-0708-02), commencing on July 1,2008. We are seeking an outstanding scientist with a strongresearch background in contemporary salivary diagnostics.Additional experience in oral cancer genetics is highly desirable.

The successful candidate will be expected to contribute to the research and teaching missions of the Division, includinginstruction of pre-doctoral and post-graduate students, and supervision of graduate students in the Section of Oral Biology.Candidates should hold DDS, DMD, MD, PhD, or equivalentdegree(s). Ideal candidates would possess dental and PhD degrees,have a research funding record and teaching experience. The position requires the ability to secure extramural funding to support an independent research program. Salary is commensuratewith education and experience.

Interested individuals should submit a letter of intent includinga statement of achievements and future goals, curriculum vitaeand the names and contact information for three references by February 15th, 2008. These materials should be submittedelectronically as one pdf file to the Oral Biology SearchCommittee at: jmartinez@dentistry.ucla.edu.

UCLA is an Equal Opportunity/Affirmative Action Employer with a strong commitment to the

achievement of excellence and diversity in its faculty.

TENURE-TRACK FACULTY POSITION IN ORAL BIOLOGY

Clinical Professor of PeriodontologyDivision of Periodontology,Department of Orofacial SciencesUniversity of California, San Francisco

The Department of Orofacial Sciences, School ofDentistry, University of California, San Francisco seeksapplicants for a full-time position as Director of thePostgraduate Program in Periodontology, in the Divisionof Periodontology. This position would be an Assistant,Associate or Full Professor in the Clinical or Clinical X series. Applicants must have a dental degree (DDS,DMD, or equivalent) and a certificate of advanced training in periodontology, and be a Diplomate of theAmerican Board of Periodontology or be Board-eligible.Experience in research, teaching, placement of dentalimplants, and conscious sedation techniques is desired.Intramural practice opportunities are available. Salaryand rank are commensurate with experience. This

position will remain open until filled, but applicationsreceived by April 1, 2008 will receive initial consideration.UCSF seeks candidates whose experience, teaching,research, or community service has prepared them to contribute to our commitment to diversity and excellence.Interested applicants should submit a letter of interest,curriculum vitae and the names of four references to: Dr.Peter Loomer, Committee Chair, University of California,San Francisco, Department of Orofacial Sciences, Box0650, San Francisco, California 94143-0650.

The University is an Equal Opportunity/AffirmativeAction Employer. All qualified applicants are encouragedto apply, including minorities and women.

Director of the Postgraduate Program in PeriodontologyDivision of Periodontology,Department of Orofacial SciencesUniversity of California, San Francisco

Dean - Boston University

Goldman School of

Dental Medicine

The search committee invites nominations and applications for the position of Dean, Boston University Goldman School of Dental Medicine. Information about the school may be found at:http://dentalschool.bu.edu/. Leading candidates will have distin-guished records of accomplishment in dental research, education, andadministrative experience. Candidates must also demonstrate an appreciation of the values and objectives of a dental school dedicated toexcellence in teaching, clinical service, research, and communityengagement. Nominees and applicants must hold a DDS/DMD (orequivalent degree in a health-related field) and have demonstratedscholarly distinction appropriate for a senior-level appointment.Competitive applicants should also possess a strong record in scholarlyactivity and mentoring, as evidenced by serving on editorial boards,current or prior grant support, publications in the peer-reviewed literature, and the success of previous trainees. Review of applicationswill begin immediately and will continue until the position is filled.Boston University is committed to building a culturally diverse facultyand strongly encourages applications from female and minority candidates and those with disabilities. Applications and/or nomina-tions should be sent to: Daniel G. Remick, MD, Chair, Dental DeanSearch Committee, c/o Kathryn Henri, Provost’s Office, 715 AlbanyStreet, Boston, MA, 02118. Electronic applications are preferred. Sendto kahenri@bu.edu.

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