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

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.

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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.

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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.

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Authors and Affiliations

Authors

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 to Leanne M Ward or L Darryl Quarles.

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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)

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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

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