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

Jian Q. Feng, Leanne M. Ward, Shiguang Liu, Yongbo Lu, Yixia Xie, Baozhi Yuan, Xijie Yu, Frank Rauch, Siobhan I. Davis, Shubin Zhang, Hector Rios, Marc K. Drezner, L. Darryl Quarles, Lynda F. Bonewald, Kenneth E. White

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1310-1315
Number of pages6
JournalNature genetics
Volume38
Issue number11
DOIs
StatePublished - Nov 23 2006

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ASJC Scopus subject areas

  • Genetics

Cite this

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. (2006). Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nature genetics, 38(11), 1310-1315. https://doi.org/10.1038/ng1905