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Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism
Open accessAbstract
The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) 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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“Impaired DMP1 function is associated with a hypomineralized bone phenotype, which can result in rickets or osteomalacia 40,41 .”
From Sex-specific gene expression signatures of calcific aortic valve stenosis in a large collection of human tissues (2026) · cites this paper as [41]
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“Mutations in genes that have highly enriched expression in osteocytes cause rare bone and mineral disorders.”
From Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease (2021) · cites this paper as [20]
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The cell biology of bone metabolism
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TNF-α Directly Enhances Osteocyte RANKL Expression and Promotes Osteoclast Formation
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“In hypophosphatemia, Dmp1 and Phex, also produced by the osteocyte, downregulate FGF-23 expression, thereby increasing phosphate reabsorption in the kidney and enabling the body to maintain normal phosphate levels and bone mineral content.((13,33)) Patients with chronic kidney disease, vitamin D deficiency, or hypopho…”
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“(4) Dmp1 null mice show major abnormalities in osteocyte morphology (Feng et al., 2006).”
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“While DMP1-derived ASARM peptides are also thought to inhibit mineralization,((30)) this complex protein also has a described role as a (positive) nucleator of mineralization,((60)) and gene deletion of Dmp1 results in disrupted mineralization patterns in vivo,((61)) implying that the type of posttranslational process…”
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“Dmp-1 null mice have also high circulatory levels of Fgf23, and showed phenotypes resembling ARHR patients (Feng et al. 2006).”
BackgroundUse it or lose it to age: A review of bone and muscle communication
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“In 2006 it was first proposed osteocytes are endocrine cells with the first example of a secreted factor being fibroblast growth factor 23, (FGF23), highly elevated in osteocytes in patients with hypophosphatemic rickets[40].”
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“hypophosphatemic rickets/osteomalacia (ADHR and ARHR) [4–6], tumor-induced rickets/osteomalacia (TIO) [7] and hypophosphatemia associated with McCune–Albright syndrome/fibrous dysplasia [8].”
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“Osteocytes act as mechanosensors of bone, and recent evidence has indicated a role for these cells in bone modeling and remodeling and phosphate homeostasis (Feng et al. 2006, Lorenz-Depiereux et al. 2006, Tatsumi et al. 2007).”
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“For example, osteocyte-specific gene deletion studies have revealed that osteocytes control bone resorption via production of the osteoclastogenic cytokine RANKL (69,70), whereas they control phosphate homeostasis via production of Dmp1 and FGF23 (71).”
BackgroundPhosphate Metabolism in Health and Disease
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“DMP-1 is arguably the most informative marker of osteocytes in vivo [12, 30, 31, 33] and has been identified as having a functional role in osteocyte metabolism of mineral [31].”
BackgroundResultMolecular mechanisms and clinical management of cancer bone metastasis
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“Dentin matrix protein 1 (DMP1) is almost exclusively expressed in mature osteocytes (26, 27).”
BackgroundEffects of PTH on osteocyte function
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“Inactivating mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) cause X-linked hypophosphatemic rickets (OMIM 307800) [10], and loss of DMP1 activity results in autosomal-recessive hypophosphatemic rickets (OMIM 241520) [11,13].”
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“FIBROBLAST GROWTH FACTOR 23 (FGF23) is a hormone released primarily by osteocytes (2, 4, 14, 38) that functions to regulate phosphate and vitamin D homeostasis through direct actions on the kidney and parathyroid (2).”
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Aubin, J. E. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373884-4.00026-4 · Cited by 194
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“…et al., 2001), autosomal dominant hypophosphatemic rickets (ADHR) (Consortium, 2000), autosomal recessive hypophosphatemic rickets/osteomalacia (ARHR) (Feng et al., 2006), and X-linked hypophosphatemic rickets (XLH) (Jonsson et al., 2003; Fukumoto and Yamashita, 2007; Yoshiko et al., 2007).”
BackgroundSelf-citationGenetic Evidence of Serum Phosphate-Independent Functions of FGF-23 on Bone
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“Similarly, in Dmp-1 null mice Fgf- 23 levels were high [ 25 ].”
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BackgroundPhosphate as a Signaling Molecule and Its Sensing Mechanism
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“Since Dmp1 is highly expressed in osteocytes and its deletion resulted in defective maturation of osteocytes in mice (85, 201), induction of Dmp1 by an increase in extracellular Pi might facilitate differentiation of osteoblasts to osteocytes.”
BackgroundThe Raine Syndrome Protein FAM20C Is a Golgi Kinase That Phosphorylates Bio-Mineralization Proteins
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“OPN is generally thought of as an inhibitor of biomineralization [13,40], but mutation of murine DMP1 causes hypophosphatemic Rickets, implicating it as a promoter of biomineralization [41,42].”
BackgroundRegulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway
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Self-citationThe skeleton as an endocrine organ
DiGirolamo, D. J., Clemens, T. L., & Kousteni, S. (2012) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2012.157 · Cited by 183
Metadata
- Authors
- Feng, J. Q., Ward, L. M., Liu, S., Lu, Y., Xie, Y., Yuan, B., Yu, X., Rauch, F., Davis, S. I., Zhang, S., Rios, H., Drezner, M. K., Quarles, L. D., Bonewald, L. F., & White, K. E.
- Affiliations
- University of Missouri–Kansas City (US)
- University of Ottawa (CA)
- University of Kansas (US)
- University of Wisconsin–Madison (US)
- Indiana University Indianapolis (US)
- McGill University (CA)
- Corresponding author
- Ward, Leanne M
- Quarles, L Darryl
- ORCID
- Venue
- Nature Genetics
- Published
- 2006-10-08
- Volume
- 38
- Issue
- 11
- Pages
- 1310-1315
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC1839871
- OpenAlex
- W2051959338
- Cited by
- 1,199
- References
- 25
- Citations by year
- 2026: 29 · 2025: 19 · 2024: 31 · 2023: 47 · 2022: 60 · 2021: 59 · 2020: 61 · 2019: 63 · 2018: 62 · 2017: 57 · 2016: 52 · 2015: 64 · 2014: 58 · 2013: 81 · 2012: 93
- FWCI
- 46.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063934, R01DK063934)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR045955, R01AR051587, AR 046798, R01AR027032, AR027032, R56AR045955, R56AR027032, P01AR046798, AR051587, AR-45955)
- National Institute of Dental and Craniofacial Research (DE 13480, R29DE013480)
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- DMP1, osteocytes, rickets, osteomalacia, phosphate homeostasis, fibroblast growth factor 23, bone mineralization, renal phosphate wasting, start codon mutation, C-terminal deletion
- MeSH terms
- Fibroblast Growth Factor-23, Adult, Animals, Bone and Bones, Calcification, Physiologic, Cells, Cultured, DNA Mutational Analysis, Female, Fibroblast Growth Factors, Humans, Kidney, Male, Mice, Inbred C57BL, Minerals, Osteocytes, Osteomalacia, Phosphates, Phosphoproteins, Rickets, Extracellular Matrix Proteins, Mice, Knockout, Mice
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