Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism (original) (raw)

Nature Genetics volume 38, pages 1310–1315 (2006)Cite this article

Abstract

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 via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS Google Scholar
  8. Liu, S. et al. Pathogenic role of Fgf23 in Hyp mice. Am. J. Physiol. Endocrinol. Metab. 291, E38–E49 (2006).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS Google Scholar
  20. Glorieux, F.H. et al. Normative data for iliac bone histomorphometry in growing children. Bone 26, 103–109 (2000).
    Article CAS Google Scholar
  21. Smith, R., Walton, R.J. & Woods, C.G. Letter: Osteoporosis of ageing. Lancet 1, 40 (1976).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS 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).
    Article CAS Google Scholar

Download references

Acknowledgements

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

Author notes

  1. Jian Q Feng, Leanne M Ward and Shiguang Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Oral Biology, University of Missouri-Kansas City, Kansas City, 64108, Missouri, USA
    Jian Q Feng, Yongbo Lu, Yixia Xie, Shubin Zhang, Hector Rios & Lynda F Bonewald
  2. Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, K1H 8L1, Ontario, Canada
    Leanne M Ward
  3. Department of Internal Medicine, The Kidney Institute & Division of Nephrology, University of Kansas Medical Center, Kansas City, 66160, Kansas, USA
    Shiguang Liu & L Darryl Quarles
  4. Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA
    Baozhi Yuan & Marc K Drezner
  5. Department of Medical & Molecular Genetics, Indiana University, Indianapolis, 46202, Indiana, USA
    Xijie Yu, Siobhan I Davis & Kenneth E White
  6. Shriners Hospital for Children, McGill University, Montreal, H3G 1A6, Quebec, Canada
    Frank Rauch

Authors

  1. Jian Q Feng
    You can also search for this author inPubMed Google Scholar
  2. Leanne M Ward
    You can also search for this author inPubMed Google Scholar
  3. Shiguang Liu
    You can also search for this author inPubMed Google Scholar
  4. Yongbo Lu
    You can also search for this author inPubMed Google Scholar
  5. Yixia Xie
    You can also search for this author inPubMed Google Scholar
  6. Baozhi Yuan
    You can also search for this author inPubMed Google Scholar
  7. Xijie Yu
    You can also search for this author inPubMed Google Scholar
  8. Frank Rauch
    You can also search for this author inPubMed Google Scholar
  9. Siobhan I Davis
    You can also search for this author inPubMed Google Scholar
  10. Shubin Zhang
    You can also search for this author inPubMed Google Scholar
  11. Hector Rios
    You can also search for this author inPubMed Google Scholar
  12. Marc K Drezner
    You can also search for this author inPubMed Google Scholar
  13. L Darryl Quarles
    You can also search for this author inPubMed Google Scholar
  14. Lynda F Bonewald
    You can also search for this author inPubMed Google Scholar
  15. Kenneth E White
    You can also search for this author inPubMed Google Scholar

Contributions

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 toLeanne M Ward or L Darryl Quarles.

Ethics declarations

Competing interests

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

Supplementary information

Rights 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). https://doi.org/10.1038/ng1905

Download citation

This article is cited by

Associated content

Bone talk

Nature Genetics News & Views 01 Nov 2006