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.
“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]
Mutations in genes that have highly enriched expression in osteocytes cause rare bone and mineral disorders.
“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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Malaval, L., Wade‐Gueye, N. M., Boudiffa, M., Fei, J., Zirngibl, R. A., Chen, F., Laroche, N., Roux, J.-P., Burt‐Pichat, B., Duboeuf, F., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071294 · Cited by 275 · see citing works
Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease
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“growth factor 23 (FGF-23), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE), may regulate each other through direct or indirect mechanisms (1;2), and circulating levels of FGF-23 are markedly elevated in patients with CKD (3).”
BackgroundOsteocyte: the unrecognized side of bone tissue
Rochefort, G. Y., Pallu, S., & Benhamou, C. L. (2010) · Osteoporosis International · doi:10.1007/s00198-010-1194-5 · Cited by 268 · see citing works
“DMP1 knockout is associated with a hypo-mineralized phenotype linked with elevated fibroblast growth factor 23 (FGF23) and defective osteocyte lacuno-canalicular network formation [25].”
Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism
Quarles, L. D. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.218 · Cited by 268 · see citing works
Self-citationCell-free 3D scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects
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The osteocyte as a signaling cell
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Identification of differentially expressed genes between osteoblasts and osteocytes
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“A specific dendritic morphology, formation of a network within mineralized matrix [46], mechanosensory ability and evidence for the expression of NPY and other ion channels, are all observations that support the notion that osteocytes can function as “neuronal” cells in bone.”
BackgroundRhee, Y., Bivi, N., Farrow, E., Lezcano, V., Plotkin, L. I., White, K. E., & Bellido, T. (2011) · Bone · doi:10.1016/j.bone.2011.06.025 · Cited by 259 · see citing works
“Osteocytes produce fibroblast growth factor-23 (FGF23) [5-8], a hormone produced in bone that plays a crucial role in phosphate (Pi) homeostasis by inhibiting its renal reabsorption [9].”
BackgroundSelf-citationMartin, A., Liu, S., David, V., Li, H., Karydis, A., Feng, J. Q., & Quarles, L. D. (2011) · The FASEB Journal · doi:10.1096/fj.10-177816 · Cited by 254 · see citing works
“Based on the similar phenotypical characteristics observed between Hyp and Dmp1 / mice (7, 32), we hypothesized that PHEX and DMP1 could regulate extracellular matrix mineralization and Fgf23 expression through a common mechanism intrinsic to the bone microenvironment.”
BackgroundMethodInfluentialSelf-citationde Beur, S. M. J. (2005) · JAMA · doi:10.1001/jama.294.10.1260 · Cited by 250 · see citing works
TNF-α Directly Enhances Osteocyte RANKL Expression and Promotes Osteoclast Formation
Marahleh, A., Kitaura, H., Ohori, F., Kishikawa, A., Ogawa, S., Shen, W.-R., Qi, J., Noguchi, T., Nara, Y., & Mizoguchi, I. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02925 · Cited by 243 · see citing works
“Osteocytes have gained popularity ever since their isolation from bone became possible (28), from there osteocytes were shown to regulate mineral metabolism (29), remodel the extracellular matrix (30), act as an endocrine cell (31), a mechanosensory cell (32), and activate osteoclastogenesis through osteocyte apoptoti…”
BackgroundDo osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited
Teti, A. M., & Zallone, A. Z. (2008) · Bone · doi:10.1016/j.bone.2008.09.017 · Cited by 245 · see citing works
“In addition, through the DMP1 [16] and FGF23[17] pathways, they form an”
BackgroundWoo, S. M., Rosser, J., Dusevich, V., Kalajzic, I., & Bonewald, L. F. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.465 · Cited by 243 · see citing works
“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…”
BackgroundSelf-citationYao, W., Cheng, Z., Busse, C., Pham, A., Nakamura, M. C., & Lane, N. E. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23454 · Cited by 241 · see citing works
Qin, C., D’Souza, R. N., & Feng, J. Q. (2007) · Journal of Dental Research · doi:10.1177/154405910708601202 · Cited by 240 · see citing works
“(4) Dmp1 null mice show major abnormalities in osteocyte morphology (Feng et al., 2006).”
BackgroundInfluentialSelf-citationAtkins, G. J., Rowe, P. S., Lim, H. P., Welldon, K. J., Ormsby, R. T., Wijenayaka, A. R., Zelenchuk, L. V., Evdokiou, A., & Findlay, D. M. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.345 · Cited by 238 · see citing works
“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…”
Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair
Paiva, K. B. S., & Granjeiro, J. M. (2017) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.05.001 · Cited by 237 · see citing works
The importance of the SIBLING family of proteins on skeletal mineralisation and bone remodelling
Staines, K. A., MacRae, V. E., & Farquharson, C. (2012) · Journal of Endocrinology · doi:10.1530/joe-12-0143 · Cited by 234 · see citing works
Razzaque, M. S., & Lanske, B. (2007) · Journal of Endocrinology · doi:10.1677/joe-07-0095 · Cited by 234 · see citing works
“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
Bonewald, L. F. (2018) · Bone · doi:10.1016/j.bone.2018.11.002 · Cited by 229 · see citing works
“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].”
BackgroundSelf-citationBiominerals—hierarchical nanocomposites: the example of bone
Beniash, E. (2010) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.105 · Cited by 231 · see citing works
Initial FGF23-Mediated Signaling Occurs in the Distal Convoluted Tubule
Farrow, E., Davis, S. I., Summers, L. J., & White, K. E. (2009) · Journal of the American Society of Nephrology · doi:10.1681/asn.2008070783 · Cited by 232 · see citing works
Self-citationShimada, T., Urakawa, I., Isakova, T., Yamazaki, Y., Epstein, M., Wesseling‐Perry, K., Wolf, M. S., Salusky, I. B., & Jüppner, H. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1603 · Cited by 230 · see citing works
Schaffler, M. B., & Kennedy, O. D. (2012) · Current Osteoporosis Reports · doi:10.1007/s11914-012-0105-4 · Cited by 227 · see citing works
Calcium and Phosphate: A Duet of Ions Playing for Bone Health
Bonjour, J. (2011) · Journal of the American College of Nutrition · doi:10.1080/07315724.2011.10719988 · Cited by 222 · see citing works
Differentiation of Osteoblasts and Osteocytes from Mesenchymal Stem Cells
Heino, T. J., & Hentunen, T. A. (2008) · Current Stem Cell Research & Therapy · doi:10.2174/157488808784223032 · Cited by 218 · see citing works
Osteocytic signalling pathways as therapeutic targets for bone fragility
Plotkin, L. I., & Bellido, T. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.71 · Cited by 206 · see citing works
Endo, I., Fukumoto, S., Ozono, K., Namba, N., Tanaka, H., Inoue, D., Minagawa, M., Sugimoto, T., Yamauchi, M., Michigami, T., et al. (2008) · Bone · doi:10.1016/j.bone.2008.02.014 · Cited by 210 · see citing works
“hypophosphatemic rickets/osteomalacia (ADHR and ARHR) [4–6], tumor-induced rickets/osteomalacia (TIO) [7] and hypophosphatemia associated with McCune–Albright syndrome/fibrous dysplasia [8].”
Carpenter, T. O., Shaw, N. J., Portale, A. A., Ward, L. M., Abrams, S. A., & Pettifor, J. M. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.101 · Cited by 206 · see citing works
Self-citationPowell, W. F., Barry, K. J., Tulum, I., Kobayashi, T., Harris, S. E., Bringhurst, F. R., & Pajevic, P. D. (2011) · Journal of Endocrinology · doi:10.1530/joe-10-0308 · Cited by 202 · see citing works
“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).”
BackgroundBasic Biology of Skeletal Aging: Role of Stress Response Pathways
Almeida, M., & O’Brien, C. A. (2013) · The Journals of Gerontology Series A · doi:10.1093/gerona/glt079 · Cited by 202 · see citing works
“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
Peacock, M. (2020) · Calcified Tissue International · doi:10.1007/s00223-020-00686-3 · Cited by 202 · see citing works
Atkins, G. J., Welldon, K. J., Halbout, P., & Findlay, D. M. (2008) · Osteoporosis International · doi:10.1007/s00198-008-0728-6 · Cited by 199 · see citing works
“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
Wang, M., Xia, F., Wei, Y., & Wei, X. (2020) · Bone Research · doi:10.1038/s41413-020-00105-1 · Cited by 200 · see citing works
Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin
Andreev, D., Liu, M., Weidner, D., Kachler, K., Faas, M., Grüneboom, A., Schlötzer-Schrehardt, U., Muñoz, L. E., Steffen, U., Grötsch, B., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134214 · Cited by 188 · see citing works
“Dentin matrix protein 1 (DMP1) is almost exclusively expressed in mature osteocytes (26, 27).”
BackgroundEffects of PTH on osteocyte function
Bellido, T., Saini, V., & Pajevic, P. D. (2013) · Bone · doi:10.1016/j.bone.2012.09.016 · Cited by 196 · see citing works
“Osteocytes also express and secrete fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate reabsorption in the kidney and that, by changing circulating levels of phosphate, also affects bone mineralization [20–24].”
Inactivation of a Novel FGF23 Regulator, FAM20C, Leads to Hypophosphatemic Rickets in Mice
Wang, X., Wang, S., Li, C., Gao, T., Liu, Y., Rangiani, A., Sun, Y., Hao, J., George, A., Lu, Y., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002708 · Cited by 197 · see citing works
“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].”
BackgroundInfluentialSelf-citationTouchberry, C., Green, T. M., Tchikrizov, V., Mannix, J., Mao, T. F., Carney, B. W., Girgis, M., Vincent, R. J., Wetmore, L. A., Dawn, B., et al. (2013) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00596.2012 · Cited by 195 · see citing works
“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).”
BackgroundSelf-citationMesenchymal Stem Cells and Osteoblast Differentiation
Aubin, J. E. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373884-4.00026-4 · Cited by 189 · see citing works
Goodman, W. G., & Quarles, L. D. (2007) · Kidney International · doi:10.1038/sj.ki.5002287 · Cited by 188 · see citing works
Self-citationOsteocyte regulation of bone mineral: a little give and take
Atkins, G. J., & Findlay, D. M. (2012) · Osteoporosis International · doi:10.1007/s00198-012-1915-z · Cited by 185 · see citing works
Role of FGFs/FGFRs in skeletal development and bone regeneration
Du, X.-L., Xie, Y.-L., Xian, C. J., & Chen, L. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24083 · Cited by 156 · see citing works
“…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
Sitara, D., Kim, S., Razzaque, M. S., Bergwitz, C., Taguchi, T., Schüler, C., Erben, R. G., & Lanske, B. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000154 · Cited by 184 · see citing works
“Similarly, in Dmp-1 null mice Fgf- 23 levels were high [ 25 ].”
BackgroundVincent, C., Findlay, D. M., Welldon, K. J., Wijenayaka, A. R., Zheng, T. S., Haynes, D. R., Fazzalari, N. L., Evdokiou, A., & Atkins, G. J. (2009) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.090305 · Cited by 183 · see citing works
“increased expression of osteocyte markers such as E11/ gp38,((45)) dentin matrix protein (DMP)-1,((46)) matrix extracellular phosphoglycoprotein (MEPE),((47)) and sclerostin((48,49)) (G.”
BackgroundPhosphate as a Signaling Molecule and Its Sensing Mechanism
Michigami, T., Kawai, M., Yamazaki, M., & Ozono, K. (2018) · Physiological Reviews · doi:10.1152/physrev.00022.2017 · Cited by 181 · see citing works
“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
Ishikawa, H., Xu, A., Ogura, E., Manning, G., & Irvine, K. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042988 · Cited by 180 · see citing works
“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
Rowe, P. S. N. (2012) · Critical Reviews™ in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v22.i1.50 · Cited by 173 · see citing works
Yuan, B., Takaiwa, M., Clemens, T. L., Feng, J. Q., Kumar, R., Rowe, P. S., Xie, Y., & Drezner, M. K. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32702 · Cited by 178 · see citing works
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 180 · see citing works
- 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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