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
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Frost, H.M. In vivo osteocyte death. J. Bone Joint Surg. Am. 42A, 138–143 (1960).
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).
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).
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).
Ling, Y. et al. DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis. J. Bone Miner. Res. 20, 2169–2177 (2005).
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).
Tenenhouse, H.S. X-linked hypophosphataemia: a homologous disorder in humans and mice. Nephrol. Dial. Transplant. 14, 333–341 (1999).
Liu, S. et al. Pathogenic role of Fgf23 in Hyp mice. Am. J. Physiol. Endocrinol. Metab. 291, E38–E49 (2006).
The ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).
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).
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).
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).
Ito, N. et al. Comparison of two assays for fibroblast growth factor (FGF)-23. J. Bone Miner. Metab. 23, 435–440 (2005).
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).
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).
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).
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).
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).
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).
Glorieux, F.H. et al. Normative data for iliac bone histomorphometry in growing children. Bone 26, 103–109 (2000).
Smith, R., Walton, R.J. & Woods, C.G. Letter: Osteoporosis of ageing. Lancet 1, 40 (1976).
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).
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).
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).
Rowe, P.S. et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics 67, 54–68 (2000).
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
Authors and Affiliations
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
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
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng1905
This article is cited by
-
Dental manifestations and treatment of hypophosphatemic rickets: A case report and review of literature
BDJ Open (2023)
-
The role of proteoglycan form of DMP1 in cranial repair
BMC Molecular and Cell Biology (2022)
-
Inflammatory macrophages interrupt osteocyte maturation and mineralization via regulating the Notch signaling pathway
Molecular Medicine (2022)
-
Biomineralization of bone tissue: calcium phosphate-based inorganics in collagen fibrillar organic matrices
Biomaterials Research (2022)
-
Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth
Nature Communications (2022)