Affinage

DMP1

Dentin matrix acidic phosphoprotein 1 · UniProt Q13316

Length
513 aa
Mass
55.8 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The DMP1 locus encodes two functionally distinct gene products: a secreted bone/dentin extracellular matrix phosphoprotein (DMP1/DSPP family) that governs mineralization and phosphate homeostasis, and a transcription factor (DMTF1/DMP1α) that functions as a tumor suppressor through the ARF-p53 pathway. The bone matrix protein DMP1 is cleaved by furin at Asp213 into 37-kDa N-terminal and 57-kDa C-terminal fragments, with the phosphorylated 57-kDa C-terminal fragment serving as the functional domain that promotes osteocyte maturation, organized hydroxyapatite mineralization, and suppression of FGF23 expression through αvβ3 integrin–FAK–MAPK and calcium–p38 signaling, thereby maintaining systemic phosphate homeostasis via a bone–renal axis (PMID:20663874, PMID:20734454, PMID:21642437, PMID:17033621). Loss-of-function mutations in human DMP1 cause autosomal recessive hypophosphatemic rickets (ARHR) through unrestrained FGF23 production by osteocytes (PMID:17033621, PMID:18559986). The transcription factor DMTF1/DMP1α binds CCCG(G/T)ATGT consensus elements and is activated by Ras–Raf–ERK and HER2–PI3K–NF-κB signaling to directly transactivate the ARF promoter and physically stabilize p53 by antagonizing Mdm2-mediated ubiquitination, functioning as a haploinsufficient tumor suppressor in lung and breast cancer, while an alternative splice isoform DMP1β acts as an oncogene promoting proliferation (PMID:8887674, PMID:10898794, PMID:11711428, PMID:22331460, PMID:25537728).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    The identification of DMP1/DMTF1 as a cyclin D-binding transcription factor recognizing CCCG(G/T)ATGT consensus sequences established the gene's dual identity as both a cell-cycle-regulated transcription factor and, separately, a matrix protein.

    Evidence Yeast two-hybrid screen, in vitro binding, Sf9 cell co-expression, and in vitro kinase assay

    PMID:8887674

    Open questions at the time
    • Endogenous target genes unknown
    • In vivo relevance of cyclin D-DMP1 interaction unresolved
    • Relationship to bone matrix DMP1 protein unclear
  2. 2000 High

    Establishing DMP1/DMTF1 as a direct transcriptional activator of ARF and showing that DMP1-null cells bypass senescence and are transformable by oncogenic Ras alone placed DMP1 upstream of the ARF-p53 tumor suppressor pathway.

    Evidence Dmp1-knockout MEFs; cell proliferation, senescence, and Ras transformation assays

    PMID:10898794

    Open questions at the time
    • Whether DMP1 activates p53 independently of ARF was unknown
    • Relevance to human cancer not yet demonstrated
  3. 2001 High

    In vivo genetic epistasis demonstrated that DMP1 is a haploinsufficient tumor suppressor whose loss accelerates Myc-driven lymphomagenesis and eliminates selection pressure for p53 or ARF mutations.

    Evidence Dmp1+/−, Dmp1−/− crossed with Eμ-Myc transgenic mice; tumor latency and mutation analysis

    PMID:11711428

    Open questions at the time
    • Mechanism of haploinsufficiency not explained at molecular level
    • Tissue-specificity of tumor-suppressive function unknown
  4. 2004 High

    Dmp1-knockout mice revealed that the bone matrix protein DMP1 is essential for postnatal chondrogenesis and osteogenesis, with severe defects in growth plate organization, chondrocyte apoptosis, and mineralization quality.

    Evidence Dmp1-null mouse; histology, TUNEL, FTIR imaging, microCT

    PMID:15590631 PMID:16294270

    Open questions at the time
    • Which DMP1 fragment mediates these effects was unknown
    • FGF23 connection not yet discovered
  5. 2005 High

    Mapping the Ras–Raf–MEK–ERK–Jun signaling cascade as the pathway activating DMP1/DMTF1 transcription, which then activates ARF, explained why DMP1-null cells resist Ras-induced senescence.

    Evidence Promoter reporter assays, ChIP for Jun proteins on Dmp1 promoter, dominant-negative/knockdown approaches in Dmp1-null cells

    PMID:15601844

    Open questions at the time
    • Other oncogenic signals that activate DMP1 not explored
    • Post-translational regulation of DMP1 protein unknown
  6. 2006 High

    The discovery that DMP1 loss causes defective osteocyte maturation and excess FGF23 production leading to renal phosphate wasting in both mice and humans with ARHR established DMP1 as the molecular basis of the bone–renal phosphate axis.

    Evidence Dmp1-null mice and human ARHR mutation analysis; serum biochemistry, immunohistochemistry, histomorphometry

    PMID:17033621 PMID:17033625

    Open questions at the time
    • Signal transduction mechanism from DMP1 to FGF23 suppression unknown
    • Whether N- or C-terminal fragment mediates FGF23 regulation unresolved
  7. 2008 High

    Identification of furin as the protease cleaving DMP1 at Asp213, and double-knockout epistasis proving that FGF23 is the causative mediator of the Dmp1-null phosphate-wasting phenotype, defined the proteolytic activation step and downstream effector.

    Evidence Furin inhibitor dose-response in cell lines; Dmp1−/−/Fgf23−/− compound knockout mice with serum biochemistry

    PMID:18559986 PMID:18728349

    Open questions at the time
    • Whether cleavage is required in vivo for skeletal rescue not yet tested
    • FAM20C-mediated phosphorylation not yet linked
  8. 2010 High

    In vivo mutagenesis of the cleavage site (D213A) proved that proteolytic processing is an obligate activation step, while transgenic rescue with the 57-kDa C-terminal fragment alone fully corrected Dmp1-null skeletal and phosphate phenotypes, identifying the C-terminal fragment as the functionally dominant domain.

    Evidence D213A knock-in and 57-kDa fragment transgenic rescue in Dmp1-null mice; radiological, biochemical, histological analysis

    PMID:20663874 PMID:20734454

    Open questions at the time
    • Whether the 37-kDa fragment has independent in vivo function unknown
    • Regulation of furin cleavage efficiency uncharacterized
  9. 2010 High

    Extracellular DMP1 was shown to signal through αvβ3 integrin–FAK–MAPK and calcium–p38 pathways to activate osteoblast differentiation transcription factors including Runx2, revealing the receptor and downstream signaling mechanism.

    Evidence Anti-integrin antibody blockade; pharmacological kinase inhibitors; calcium chelation; Western blot for FAK/ERK/JNK/p38 phosphorylation

    PMID:20841352 PMID:21642437

    Open questions at the time
    • Direct binding of DMP1 to integrin not reconstituted biochemically
    • Relative contribution of integrin vs. calcium signaling in vivo unknown
  10. 2011 High

    Phosphorylation was established as the critical post-translational modification controlling DMP1's mineralization activity: phosphorylated DMP1 drives organized collagen mineralization while non-phosphorylated DMP1 does not, and distinct localizations of N- and C-terminal fragments correlate with different mineralization zones.

    Evidence In vitro collagen fibril mineralization with phosphorylated vs. dephosphorylated DMP1; fragment-specific immunohistochemistry and FRET in teeth

    PMID:18854597 PMID:21736373

    Open questions at the time
    • Identity of the kinase responsible for DMP1 phosphorylation not yet confirmed in vivo
    • Structural basis of phosphorylation-dependent mineral nucleation unknown
  11. 2012 High

    Discovery that DMP1/DMTF1 physically interacts with p53 and antagonizes Mdm2-mediated ubiquitination independently of ARF established a second, ARF-independent mechanism of tumor suppression.

    Evidence Reciprocal co-immunoprecipitation; ubiquitination assay; nuclear fractionation; reporter assays in p53−/−;Arf−/− cells

    PMID:22331460

    Open questions at the time
    • Relative contribution of ARF-dependent vs. p53-direct pathways in different tumor types unknown
    • Structural basis of DMP1-p53 interaction unresolved
  12. 2015 High

    The oncogenic DMP1β splice isoform was shown to drive mammary tumorigenesis in transgenic mice, establishing that alternative splicing of the DMTF1 locus generates opposing tumor-suppressive (DMP1α) and tumor-promoting (DMP1β) proteins.

    Evidence MMTV-DMP1β transgenic mice; cell proliferation assays; RNA-seq; histopathology

    PMID:25537728

    Open questions at the time
    • Molecular mechanism by which DMP1β promotes proliferation not defined
    • Splicing regulation determining α/β ratio unknown
  13. 2016 Medium

    FAM20C was identified as the Golgi kinase that phosphorylates the DMP1 C-terminal fragment in osteocytes before secretion, and glycosylation of the N-terminal fragment was shown essential for condylar cartilage chondrogenesis, clarifying the post-translational maturation pathway.

    Evidence Co-localization immunoelectron microscopy of FAM20C and phospho-DMP1 in Golgi; S89G glycosylation-site knock-in mouse with TMJ phenotyping

    PMID:27614627 PMID:28759313

    Open questions at the time
    • Direct in vitro kinase assay for FAM20C on DMP1 not shown in these studies
    • Functional interplay between glycosylation and phosphorylation unexplored
  14. 2019 High

    DMP1 supplementation in a CKD mouse model prevented osteocyte apoptosis, corrected bone mass, attenuated NFAT-driven FGF23 transcription, and improved cardiac outcomes and survival, demonstrating therapeutic potential and identifying NFAT as a transcriptional target of DMP1-mediated FGF23 suppression.

    Evidence Genetic and pharmacological DMP1 supplementation in Col4a3−/− CKD mice; echocardiography, TUNEL, FGF23 ELISA, NFAT reporter assay

    PMID:31044094

    Open questions at the time
    • Precise signaling link from DMP1 to NFAT inhibition not fully mapped
    • Whether DMP1 supplementation is viable in human CKD unaddressed
  15. 2024 High

    An unexpected non-skeletal role was uncovered: DMP1-expressing astrocytes regulate blood–brain barrier integrity by transferring mitochondria to endothelial cells via Mfn2-dependent mechanisms at astrocyte endfeet.

    Evidence Conditional Mfn2 deletion in Dmp1-Cre astrocytes; live imaging of mitochondrial transfer; BBB permeability assays; electron microscopy

    PMID:38941455

    Open questions at the time
    • Whether astrocytic DMP1 protein itself participates in mitochondrial transfer or merely marks these cells is unclear
    • Relevance to neurodegenerative disease not yet established
    • Independence from Cre-line ectopic expression not fully ruled out

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of DMP1 mineral nucleation, the full repertoire of DMP1 signaling receptors in osteocytes, the splicing regulatory mechanism governing DMP1α/β ratio, and whether DMP1 protein functions cell-autonomously in astrocytes remain unresolved.
  • No crystal or cryo-EM structure of DMP1 or its fragments
  • Direct receptor for DMP1 on osteocytes not definitively identified
  • Splicing factors controlling DMP1α vs. DMP1β unknown
  • Astrocyte DMP1 protein function vs. Cre-driver artifact not distinguished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0031012 extracellular matrix 5 GO:0005634 nucleus 4 GO:0005576 extracellular region 3 GO:0005794 Golgi apparatus 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3
Partners
CCND1CDKN2AFAM20CFGF23FURINHSPA5ITGB3TP53

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 DMP1 (cyclin D-interacting myb-like protein 1, also called DMTF1 in the tumor-suppressor context) was identified as a novel transcription factor that binds specifically to the nonamer DNA consensus sequence CCCG(G/T)ATGT to activate transcription. DMP1 binds directly to D-type cyclins in vitro and in insect Sf9 cells, and can be phosphorylated by cyclin D-dependent kinases (CDK4/CDK6), suggesting its transcriptional activity is regulated by cell-cycle kinases in an RB-independent manner. Yeast two-hybrid screen; in vitro binding assay; insect cell co-expression; in vitro kinase assay Molecular and cellular biology High 8887674
1998 DMP1 (DMTF1) directly binds to and activates the CD13/aminopeptidase N (APN) promoter; this activation requires both the intact DNA-binding and transactivation domains of DMP1. D-type cyclins antagonize DMP1-mediated transcription of CD13/APN in a CDK-independent manner. DMP1 synergizes with c-Myb at the CD13/APN promoter, and endogenous DMP1 was shown to bind this element in nuclear lysates. Reporter gene (luciferase) transactivation assay; domain deletion mutagenesis; electrophoretic mobility shift assay (EMSA); nuclear lysate binding The Journal of biological chemistry High 9786929
2000 DMP1 (DMTF1) induces ARF tumor suppressor gene expression in mouse fibroblasts, leading to p53-dependent cell cycle arrest. DMP1-null MEFs fail to upregulate p19ARF, Mdm2, and p53 during passaging, do not senesce, and can be transformed by oncogenic Ha-Ras alone, placing DMP1 upstream of ARF in the ARF-p53 tumor suppressor pathway. Genetic knockout (DMP1-null MEFs); cell proliferation and transformation assays; Western blot; oncogenic Ras transformation assay Genes & development High 10898794
2001 DMP1 (DMTF1) is a transcriptional activator of ARF and acts as a haplo-insufficient tumor suppressor; Dmp1 loss accelerates E-mu-Myc-induced B-cell lymphomas and obviates selection for p53 mutations or ARF deletion, demonstrating that DMP1 is a physiological regulator of the ARF-p53 pathway in vivo. Genetic epistasis in mice (Dmp1-/-, Dmp1+/-, E-mu-Myc); tumor latency analysis; mutation sequencing Genes & development High 11711428
2003 DMP1 (bone matrix protein) mRNA and protein expression in osteocytes is upregulated by mechanical loading in vivo; osteocyte DMP1 mRNA increased up to 3.7-fold within 6 hours to 7 days of tooth movement-induced mechanical loading, while osteoblast DMP1 was transiently decreased, suggesting DMP1 participates in the osteocyte response to mechanical stimuli. In situ hybridization; immunocytochemistry; mouse tooth movement model Journal of bone and mineral research Medium 12733719
2004 Dmp1-deficient mice develop severe postnatal chondrogenesis defects including expanded proliferating and hypertrophic zones, reduced apoptosis in hypertrophic chondrocytes, and impaired blood vessel invasion in epiphyses, establishing that the bone matrix protein DMP1 is essential for normal postnatal chondrogenesis and subsequent osteogenesis. Dmp1 knockout mouse; histology; immunohistochemistry; TUNEL assay; microCT The Journal of biological chemistry High 15590631
2005 DMP1 (DMTF1 transcription factor) promoter is activated by oncogenic Ha-Ras(V12) through Raf-MEK-ERK signaling, and Jun family proteins (c-Jun, JunB) bind a Ras-responsive element in the DMP1 promoter and are required for this activation. DMP1 in turn binds to a Ras-responsive element on the ARF promoter, so that Ras/Raf activation of ARF is indirectly mediated through DMP1, explaining resistance of Dmp1-null cells to Ras-induced senescence. Promoter reporter assay; chromatin immunoprecipitation (ChIP); dominant negative/knockdown of Jun proteins; primary Dmp1-null cell assays Molecular and cellular biology High 15601844
2005 FTIR imaging of Dmp1-null mouse tibia showed significantly decreased mineral-to-matrix ratio and increased mineral crystallinity compared to wild-type, demonstrating that the bone matrix protein DMP1 has a direct role in regulating the extent and quality of bone mineralization in vivo. FTIR imaging spectroscopy; microCT; histology; Dmp1 knockout mouse Journal of bone and mineral research High 16294270
2006 Loss of the bone matrix protein DMP1 in mice and in humans with autosomal recessive hypophosphatemic rickets (ARHR) causes defective osteocyte maturation and increased FGF23 expression in osteocytes, leading to renal phosphate wasting, hypophosphatemia, and osteomalacia; this established a bone-renal axis mediated by osteocyte-derived FGF23. Dmp1-null mouse; human genetic mutation analysis; immunohistochemistry; serum biochemistry; histomorphometry Nature genetics High 17033621 17033625
2006 Re-expression of DMP1 under an early odontoblast (Col1a1) promoter fully rescued mineralization, dentinal tubule, and third molar development defects in Dmp1-null mice, while expression only in mature odontoblasts (Dspp promoter) gave partial rescue, establishing that DMP1 is required early in odontoblast differentiation and controls both dentin tubular formation and mineral apposition rate. Transgenic rescue in Dmp1-null mice; fluorochrome labeling; histology; dental phenotyping Developmental biology High 17196192
2007 DMP1 (DMTF1 transcription factor) promoter is repressed by anthracyclins and UV-C through NF-κB subunit p65 binding to the DMP1 promoter, leading to decreased ARF levels; this establishes a p65-dependent mechanism of p53 inactivation through suppression of the DMP1-ARF pathway. Promoter reporter assay; ChIP; siRNA knockdown of p65; RT-PCR; Western blot Oncogene High 17546045
2007 ASARM peptides derived from DMP1 (and MEPE) are potent inhibitors of mineralization (minhibins); a synthetic PHEX peptide (SPR4) binds directly to ASARM peptides (demonstrated by surface plasmon resonance and NMR), preventing their mineralization-inhibiting activity. Massive degradation of DMP1 protein in HYP bone releases these peptides and is the primary mechanism of the mineralization defect. Surface plasmon resonance; 2D 1H/15N NMR; bone marrow stromal cell co-culture mineralization assay; anti-ASARM antibody neutralization; Western blot Endocrinology High 18162525
2007 DMP1 (DMTF1) loss is mutually exclusive with ARF/p53 loss in lung cancer and Dmp1 deletion accelerates K-ras-induced lung tumorigenesis, with ~40% of K-ras tumors from wild-type mice showing Dmp1 LOH, confirming DMP1 as a pivotal tumor suppressor acting through ARF/p53 in lung cancer. K-ras transgenic mouse crossed to Dmp1 null; LOH analysis; tumor sequencing; survival analysis Cancer cell High 17936562
2008 DMP1 (bone matrix protein) controls FGF23 production by osteocytes; in Dmp1(-/-)/Fgf23(-/-) double-null mice, elevated FGF23 from Dmp1 loss is responsible for the hypophosphatemia, renal phosphate wasting, and diffuse osteomalacia, as loss of Fgf23 converts the Dmp1-null rickets phenotype to that of Fgf23-null mice. Compound knockout mice (Dmp1-/-, Fgf23-/-); serum biochemistry; histomorphometry; bone imaging American journal of physiology. Endocrinology and metabolism High 18559986
2008 DMP1 protein is cleaved by furin protease at residue Asp213 into a 37-kDa N-terminal and a 57-kDa C-terminal fragment; furin inhibitor (decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone) blocks this cleavage in a dose-dependent manner in CHO cells. PHEX co-expression did not affect DMP1 cleavage, indicating PHEX is not required for DMP1 processing. Cell-based expression in 293EBNA, CHO, 2T3 cells; furin inhibitor treatment; Western blot; transgenic mice Cells, tissues, organs High 18728349
2008 DMP1 ARHR mutations alter cellular processing: the M1V mutation prevents DMP1 from entering the trans-Golgi network and secretory pathway, while the 1484-1490del mutation still localizes to the TGN but the 33 non-native residues at the C-terminus likely compromise DMP1 processing. DMP1 mRNA and protein are upregulated 12-fold by 1,25(OH)2 vitamin D treatment in UMR-106 cells. Immunofluorescence; confocal microscopy; Western blot; cell transfection; RT-PCR Bone Medium 19007919
2009 MMP-2 (matrix metalloproteinase-2) cleaves DMP1 (bone/dentin matrix protein), both in recombinant form and in its native state within dentin matrix. Cleavage produces a C-terminal fragment that contains the ASARM domain and DNA-binding site. This C-terminal MMP-2 cleavage product promotes differentiation of dental pulp stem/progenitor cells to an odontoblast phenotype in vitro and induces reparative dentin bridge formation in vivo in injured rat pulp. In vitro protease cleavage assay; recombinant peptide treatment of dental pulp stem cells; in vivo rat pulp injury model; immunohistochemistry European cells & materials Medium 19908197
2010 The 57-kDa C-terminal fragment of DMP1 (bone matrix protein) is the functional domain: proteolytic processing of full-length DMP1 at Asp213 is an activation step essential for its biological role in osteogenesis. Transgenic mice expressing the uncleavable D213A-DMP1 mutant in a Dmp1-KO background fail to rescue skeletal defects, while normal DMP1 transgene expression fully rescues. Transgenic mice (D213A point mutant); crossbreeding with Dmp1-KO; radiological, biochemical, and histological analysis; Western blot The Journal of biological chemistry High 20663874
2010 DMP1 (bone matrix protein) signals via cell-surface αvβ3 integrin: extracellular DMP1 triggers focal adhesion formation in human mesenchymal stem cells and osteoblast-like cells, stimulates phosphorylation of focal adhesion kinase (FAK), and activates downstream MAPK pathways (ERK, JNK). Phosphorylated JNK translocates to the nucleus and up-regulates c-Jun-dependent transcription. This signaling is blocked by anti-αvβ3 integrin antibody. Cell-based signaling assays; focal adhesion staining; Western blot for FAK/ERK/JNK phosphorylation; anti-integrin antibody inhibition; nuclear fractionation The Journal of biological chemistry High 21642437
2010 DMP1 (bone matrix protein) mediates calcium signaling in osteoblast differentiation: endocytosed DMP1 raises cytosolic calcium levels, triggering store-operated calcium release and activation of p38 MAPK, which translocates to the nucleus to phosphorylate transcription factors that up-regulate Runx2, a key osteoblast differentiation factor. Calcium chelation; pharmacological inhibition of p38 MAPK; dominant-negative plasmid; Western blot; RT-PCR for Runx2; endocytosis assays The Journal of biological chemistry High 20841352
2010 The three forms of DMP1 (full-length, 37-kDa N-terminal fragment, 57-kDa C-terminal fragment, and DMP1-PG) have distinct effects on hydroxyapatite (HA) formation: 37K and 57K fragments are promoters of HA formation and growth, while DMP1-PG is an inhibitor. Full-length DMP1 undergoes conformational change upon HA binding, whereas the fragments do not. Gelatin-gel in vitro mineralization system; FTIR spectroscopy of secondary structure; Ca2+ and HA binding assays Journal of dental research High 20200415
2010 DMP1 (DMTF1) directly interacts with HER2/neu through the PI3K-Akt-NF-κB pathway: NF-κB subunits p65 and p52 bind to the Dmp1 promoter upon HER2/neu overexpression, activating DMP1 transcription, which in turn activates ARF transcription. This pathway is required for HER2/neu-induced tumor suppression in mammary cells; Dmp1 loss accelerates mammary tumorigenesis in MMTV-neu mice. ChIP (p65/p52 binding to Dmp1 promoter; Dmp1 binding to Arf promoter); transgenic mouse tumor model; genetic crossing Cancer research High 21062982
2011 The 57-kDa C-terminal fragment of DMP1 (bone matrix protein) is the functional domain controlling osteocyte maturation and phosphate homeostasis: transgenic expression of the 57-kDa C-terminal fragment alone in Dmp1-null mice fully rescued growth plate defects, osteomalacia, abnormal osteocyte maturation, lacunocanalicular system, elevated FGF23 expression, and hypophosphatemia. Transgenic rescue experiment; Col1 promoter-driven 57-kDa fragment in Dmp1-null mice; serum biochemistry; histomorphometry; immunohistochemistry Journal of bone and mineral research High 20734454
2011 DMP1 processing into fragments is essential for dentin and jaw formation: mice expressing only uncleavable D213A-DMP1 transgene (Dmp1-KO/D213A-Tg) showed absence of DMP1 cleavage and failed to rescue dentin, cementum, and alveolar bone defects of Dmp1-KO mice, confirming proteolytic activation is required in dentinogenesis. Transgenic mouse (D213A knock-in with Dmp1-KO background); dental and bone phenotyping; Western blot Journal of dental research High 21297011
2011 PHEX and DMP1 (bone matrix proteins) regulate FGF23 expression in osteocytes through a common pathway involving FGFR signaling: compound Phex/Dmp1 double-mutant mice display non-additive FGF23 elevations, and pharmacological FGFR inhibition (SU5402) prevents the increase in FGF23 mRNA in both Hyp and Dmp1-/- bone marrow stromal cells. Compound mutant mice (Hyp/Dmp1-/-); microarray; pharmacological FGFR inhibition; RT-PCR; serum biochemistry FASEB journal High 21507898
2011 Phosphorylation of DMP1 (bone/dentin matrix protein) profoundly determines its mineralization-regulating activity: phosphorylated DMP1 facilitates organized mineralization of collagen fibrils and induces formation of organized mineral bundles even in the absence of collagen, while non-phosphorylated DMP1 does not, demonstrating that primary structure and phosphorylation uniquely determine SIBLING function in biomineralization. In vitro collagen fibril mineralization assay; electron microscopy; comparison of phosphorylated vs. dephosphorylated protein forms Biomacromolecules High 21736373
2011 DMP1 (bone matrix protein) N-terminal and C-terminal fragments have distinct subcellular and extracellular localizations: the N-terminal fragment localizes to predentin/proliferation zones, while the C-terminal fragment localizes to mineralized dentin/ossification zones. FRET analysis confirms colocalization in odontoblasts and predentin, and biochemical analysis shows predentin is rich in DMP1-PG while mineralized dentin contains predominantly the C-terminal fragment. Antibody-specific immunohistochemistry; confocal microscopy; FRET; biochemical fractionation of bovine teeth The journal of histochemistry and cytochemistry Medium 18854597
2012 DMP1 (DMTF1 transcription factor) physically interacts with p53 via its DNA-binding domain and the C-terminus of p53. DMP1 expression antagonizes Mdm2-mediated ubiquitination of p53 and promotes p53 nuclear localization, thereby activating p53 target genes independently of ARF. This Arf-independent DMP1-p53 interaction provides a second mechanism of tumor suppression. Co-immunoprecipitation; ubiquitination assay; nuclear fractionation; reporter gene assay in p53-/-;Arf-/- cells; genotoxic stress assays Cancer research High 22331460
2012 DMP1 (DMTF1) overexpression in normal cells activates both Arf and Ink4a promoters in a DMP1-dependent manner when combined with cyclin D1, leading to apoptosis or G2/M delay; this activation is absent in Dmp1-deficient cells, establishing that cyclin D1-induced Ink4a/Arf expression depends on DMP1. Reporter gene assay; genetic crossing (MMTV-cyclin D1 × Dmp1-null); RT-PCR; flow cytometry; mammary tumor analysis The American journal of pathology Medium 23938323
2012 DMP1 (bone matrix protein) has an anti-apoptotic role in high-phosphate environments: in Dmp1-/-/Klotho-/- double-null mice, loss of DMP1 dramatically elevated osteocyte apoptosis and ectopic calcification in blood vessels and kidneys compared to Klotho-/- mice alone, while mineral parameters matched Klotho-/- controls. Compound knockout mice; TUNEL assay; immunohistochemistry; microCT; histomorphometry; serum biochemistry PloS one Medium 22879941
2013 DMP1 (bone/dentin matrix protein) controls dentinogenesis through regulation of DSPP: endogenous DSPP expression is markedly reduced in Dmp1-KO mice; transgenic DSPP expression rescues Dmp1-KO tooth and alveolar bone defects; and DMP1 and its 57-kDa C-terminal fragment significantly up-regulate the Dspp promoter in a mesenchymal cell line in vitro, establishing DSPP as a downstream effector of DMP1 in dentinogenesis. Transgenic rescue (DSPP Tg in Dmp1-KO background); promoter reporter assay; histology; biochemical analysis The Journal of biological chemistry High 23349460
2014 DMP1 (bone matrix protein) directly and negatively regulates FGF23 production in osteocytes via FAK-mediated MAPK signaling: exogenous DMP1 added to UMR-106 and MC3T3-E1 osteocyte-like cells significantly reduced FGF23 production; this effect was reversed by FAK inhibitor or MEK inhibitor, and DMP1 treatment activated FAK, ERK, and p38 phosphorylation. Recombinant DMP1 treatment of osteoblast/osteocyte-like cells; pharmacological kinase inhibitors; Western blot for FAK/ERK/p38 phosphorylation; immunohistochemistry in vivo BoneKEy reports Medium 24991406
2015 DMP1β, an alternative splice isoform of the DMP1 locus (DMTF1), acts as an oncogene: overexpression of DMP1β in non-tumorigenic mammary epithelial cells increased proliferation, and MMTV-DMP1β transgenic mice developed mammary gland hyperplasia and multifocal tumors, establishing that alternative splicing of the DMP1 locus generates a tumor-promoting isoform (DMP1β) alongside the tumor-suppressive DMP1α. MMTV-DMP1β transgenic mouse; cell proliferation assays; RNA-seq; Western blot; siRNA knockdown; histopathology The Journal of pathology High 25537728
2015 PTH downregulates DMP1 gene transcription (~85%) and protein expression (~30%) in cementoblasts via the cAMP/protein kinase A (PKA) pathway; 1,25(OH)2D3 also represses DMP1 via the vitamin D receptor pathway; both hormones share a common set of regulated target genes related to mineral homeostasis. RT-PCR; Western blot; cAMP/PKA inhibitor experiments; RNA-seq; PCR array; immunohistochemistry in vivo (PTH-treated mice) Journal of dental research High 26276370
2016 Glycosylation of DMP1 (bone matrix protein N-terminal fragment as DMP1-PG) is essential for mandibular condylar cartilage chondrogenesis: knock-in mice with a glycosylation site mutation (S89G) showed reduced DMP1-PG, thinner cartilage, disordered chondrocyte arrangement, earlier onset of TMJ osteoarthritis-like changes, and downregulated TGFβ signaling molecules in condylar cartilage. Knock-in mouse (S89G-DMP1); histology; immunohistochemistry; Western blot; OA scoring Journal of dental research High 28759313
2016 Phosphorylation of DMP1 C-terminal fragment is carried out by Golgi-localized kinase FAM20C within osteocytes: FAM20C and phosphorylated C-terminal DMP1 co-localize in the Golgi of osteoblastic/young osteocytes; phosphorylated C-terminal DMP1 is then secreted into the pericanalicular matrix, where it likely promotes mineralization by recruiting calcium ions. Immunohistochemistry; immunofluorescence; double-labeling immunoelectron microscopy; in vivo rat bone analysis Histochemistry and cell biology Medium 27614627
2017 A mutation in the Dmp1 gene (bone matrix protein) creates a lower set point for extracellular phosphate, maintained through regulation of FGF23 cleavage and expression: Dmp1-KO/Galnt3-KO double-null mice showed markedly elevated FGF23 expression and circulating levels in response to improved phosphorus levels, demonstrating that DMP1 loss alters phosphate sensing that governs FGF23 regulation. Compound knockout mice (Dmp1-KO/Galnt3-KO); serum biochemistry; FGF23 ELISA; bone microCT; RT-PCR Endocrinology High 28005411
2019 DMP1 (bone matrix protein) prevents osteocyte apoptosis and maintains osteocyte network connectivity; in a CKD mouse model (Col4a3-/-), DMP1 supplementation prevented osteocyte apoptosis, preserved osteocyte networks, corrected bone mass, partially lowered FGF23 by attenuating NFAT-induced FGF23 transcription, and prevented left ventricular hypertrophy and improved survival. Genetic DMP1 overexpression and pharmacological supplementation in Col4a3-/- CKD mice; echocardiography; histomorphometry; TUNEL; FGF23 ELISA; NFAT reporter assay Bone research High 31044094
2019 DMP1 (bone matrix protein) interacts with GRP78 at the plasma membrane of periodontal ligament stem cells; DMP1-GRP78 complex is internalized via the caveolin pathway and trafficked through early and late endosomes (Rab5, Rab7) to ultimately deliver DMP1 to the nucleus, where it promotes osteogenic differentiation. Total internal reflection fluorescence microscopy; confocal microscopy; endosome co-localization (Rab5, Rab7); co-immunoprecipitation (DMP1-GRP78); caveolin pathway inhibition; nuclear fractionation; RT-PCR osteogenic markers Frontiers in physiology Medium 31572220
2024 DMP1-expressing astrocytes regulate blood-brain barrier (BBB) integrity by transferring mitochondria to endothelial cells via astrocyte endfeet; deletion of Mfn2 in Dmp1-expressing astrocytes inhibits mitochondrial transfer and causes BBB leakage, and age-associated reduction in MFN2 in astrocytes reduces transfer efficiency and compromises BBB integrity. Conditional Mfn2 deletion in Dmp1-Cre astrocytes; live imaging of mitochondrial transfer; BBB permeability assays; electron microscopy Science advances High 38941455

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nature genetics 860 17033621
2006 DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nature genetics 372 17033625
2007 DMP1-targeted Cre expression in odontoblasts and osteocytes. Journal of dental research 291 17384025
2011 Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 205 21507898
2009 Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 197 19679205
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