Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism


The osteocyte, a terminally differentiated cell comprising 90%–95% of all bone cells1,2, may have multiple functions, including acting as a mechanosensor in bone (re)modeling3. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes4 and, when deleted in mice, results in a hypomineralized bone phenotype5. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (Pi) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: DMP1 mutations, osteomalacia and a defective osteocyte lacunocanalicular network in ARHR.
Figure 2: Dmp1-null mice show skeletal abnormalities, rickets and elevated FGF23.
Figure 3: Dmp1-null mice show defects in mineralization.
Figure 4: Defective osteoblast-to-osteocyte differentiation and maturation in Dmp1-null mice.
Figure 5: Defective organization of osteocyte lacunae and lacunocanalicular walls in Dmp1-null mice.
Figure 6: High-phosphate diet rescues the rickets but not the osteomalacic feature of the Dmp1-null phenotype.


  1. Frost, H.M. In vivo osteocyte death. J. Bone Joint Surg. Am. 42A, 138–143 (1960).

    Article  Google Scholar 

  2. Palumbo, C., Palazzini, S., Zaffe, D. & Marotti, G. Osteocyte differentiation in the tibia of newborn rabbit: an ultrastructural study of the formation of cytoplasmic processes. Acta Anat. (Basel) 137, 350–358 (1990).

    CAS  Article  Google Scholar 

  3. Pead, M.J. & Lanyon, L.E. Indomethacin modulation of load-related stimulation of new bone formation in vivo. Calcif. Tissue Int. 45, 34–40 (1989).

    CAS  Article  Google Scholar 

  4. Toyosawa, S. et al. Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts. J. Bone Miner. Res. 16, 2017–2026 (2001).

    CAS  Article  Google Scholar 

  5. Ling, Y. et al. DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis. J. Bone Miner. Res. 20, 2169–2177 (2005).

    CAS  Article  Google Scholar 

  6. The Hyp Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat. Genet. 11, 130–136 (1995).

  7. Tenenhouse, H.S. X-linked hypophosphataemia: a homologous disorder in humans and mice. Nephrol. Dial. Transplant. 14, 333–341 (1999).

    CAS  Article  Google Scholar 

  8. Liu, S. et al. Pathogenic role of Fgf23 in Hyp mice. Am. J. Physiol. Endocrinol. Metab. 291, E38–E49 (2006).

    CAS  Article  Google Scholar 

  9. The ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).

  10. Fisher, L.W. & Fedarko, N.S. Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect. Tissue Res. 44 (Suppl.), 33–40 (2003).

    CAS  Article  Google Scholar 

  11. D'Souza, R.N. et al. Gene expression patterns of murine dentin matrix protein 1 (Dmp1) and dentin sialophosphoprotein (DSPP) suggest distinct developmental functions in vivo. J. Bone Miner. Res. 12, 2040–2049 (1997).

    CAS  Article  Google Scholar 

  12. Feng, J.Q. et al. The Dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development. J. Dent. Res. 82, 776–780 (2003).

    CAS  Article  Google Scholar 

  13. Ito, N. et al. Comparison of two assays for fibroblast growth factor (FGF)-23. J. Bone Miner. Metab. 23, 435–440 (2005).

    CAS  Article  Google Scholar 

  14. Ye, L. et al. Deletion of dentin matrix protein-1 leads to a partial failure of maturation of predentin into dentin, hypomineralization, and expanded cavities of pulp and root canal during postnatal tooth development. J. Biol. Chem. 279, 19141–19148 (2004).

    CAS  Article  Google Scholar 

  15. Ye, L. et al. Dmp1-deficient mice display severe defects in cartilage formation responsible for a chondrodysplasia-like phenotype. J. Biol. Chem. 280, 6197–6203 (2005).

    CAS  Article  Google Scholar 

  16. Zhang, K. et al. E11/gp38 selective expression in osteocytes: regulation by mechanical strain and role in dendrite elongation. Mol. Cell. Biol. 26, 4539–4552 (2006).

    CAS  Article  Google Scholar 

  17. Butler, W.T., Brunn, J.C., Qin, C. & McKee, M.D. Extracellular matrix proteins and the dynamics of dentin formation. Connect. Tissue Res. 43, 301–307 (2002).

    CAS  Article  Google Scholar 

  18. Eicher, E.M., Southard, J.L., Scriver, C.R. & Glorieux, F.H. Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets. Proc. Natl. Acad. Sci. USA 73, 4667–4671 (1976).

    CAS  Article  Google Scholar 

  19. Marie, P.J. & Glorieux, F.H. Relation between hypomineralized periosteocytic lesions and bone mineralization in vitamin D-resistant rickets. Calcif. Tissue Int. 35, 443–448 (1983).

    CAS  Article  Google Scholar 

  20. Glorieux, F.H. et al. Normative data for iliac bone histomorphometry in growing children. Bone 26, 103–109 (2000).

    CAS  Article  Google Scholar 

  21. Smith, R., Walton, R.J. & Woods, C.G. Letter: Osteoporosis of ageing. Lancet 1, 40 (1976).

    CAS  Article  Google Scholar 

  22. Feng, J.Q. et al. The Dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft tissues during development. J. Dent. Res. 82, 776–780 (2003).

    CAS  Article  Google Scholar 

  23. McKee, M.D., Glimcher, M.J. & Nanci, A. High-resolution immunolocalization of osteopontin and osteocalcin in bone and cartilage during endochondral ossification in the chicken tibia. Anat. Rec. 234, 479–492 (1992).

    CAS  Article  Google Scholar 

  24. Feng, J.Q. et al. Dentin matrix protein 1, a target molecule for Cbfa1 in bone, is a unique bone marker gene. J. Bone Miner. Res. 17, 1822–1831 (2002).

    CAS  Article  Google Scholar 

  25. Rowe, P.S. et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics 67, 54–68 (2000).

    CAS  Article  Google Scholar 

Download references


We greatly appreciate the participation of all kindred members. We acknowledge the advice and experimental assistance of P.S.N. Rowe from the Kansas University Medical Center at Kansas City. The authors appreciate the use of the University of Missouri-Kansas City SEM Facility (J.D. Eick, Director). This study was supported by US National Institutes of Health grants to J.Q.F. (DE13480; AR051587; AR046798), K.E.W. (DK063934), M.K.D. (AR027032), L.D.Q. (AR-45955) and L.F.B. (AR046798); a Canadian Institutes for Health Research Investigator Award and a Canadian Child Health Clinician Scientist Program Award to L.M.W.; Shriners of North America (F.R.); a sub-award from the Center of Biomedical Research Excellence in Protein Structure and Function (COBRE-PSF) supported by the National Center for Research Resources (NCRR) to S.L.; Indiana Genomics Initiative funds to K.E.W. and a Chancellor Fellowship from the University of Missouri-Kansas City to Y.L.

Author information

Authors and Affiliations



L.M.W. performed clinical assessment of kindreds; K.W., S.I.D. and X.Y. performed the human genetic studies; F.R. provided patient biopsies; J.Q.F., Y.L., Y.X., S.Z., H.R. and L.F.B. characterized the Dmp1-null osteocyte phenotype; S.L., B.Y., M.D. and L.D.Q. provided the mouse FGF23 data and J.Q.F., L.M.W., L.F.B. and K.W. composed the manuscript.

Corresponding authors

Correspondence to Leanne M Ward or L Darryl Quarles.

Ethics declarations

Competing interests

K.E.W. receives royalties for licensing FGF23 to Kirin Pharmaceuticals, Inc.

Supplementary information

Supplementary Fig. 1

Complexity of the osteocyte lacunocanalicular system. (PDF 629 kb)

Supplementary Fig. 2

High-phosphate diet does not completely rescue the osteomalacia in Dmp1-null mice. (PDF 712 kb)

Supplementary Table 1

Comparison of biochemistry data for ARHR and Dmp1-null mice. (PDF 23 kb)

Supplementary Table 2

Primer sequences used for real-time PCR. (PDF 7 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Feng, J., Ward, L., Liu, S. et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 38, 1310–1315 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing