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 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.

• Authors: 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
• Journal: Nature genetics (Nat Genet) Vol. 38 Issue 11 Pg. 1310-5 (Nov 2006) ISSN: 1061-4036 [Print] United States
• PMID: 17033621 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DMP1 protein, human
• Extracellular Matrix Proteins
• FGF23 protein, human
• Fgf23 protein, mouse
• Minerals
• Phosphates
• Phosphoproteins
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23

Topics

• Adult
• Animals
• Bone and Bones (pathology)
• Calcification, Physiologic (genetics, physiology)
• Cells, Cultured
• DNA Mutational Analysis
• Extracellular Matrix Proteins (genetics)
• Female
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (blood)
• Humans
• Kidney (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Minerals (metabolism)
• Osteocytes (pathology, physiology)
• Osteomalacia (blood, genetics, pathology)
• Phosphates (metabolism)
• Phosphoproteins (genetics)
• Rickets (blood, genetics, pathology)