Nature Genetics
- 38, 1310 - 1315 (2006)
Published online: 8 October 2006; | doi:10.1038/ng1905
Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolismJian Q Feng1, 7, Leanne M Ward2, 7, Shiguang Liu3, 7, Yongbo Lu1, Yixia Xie1, Baozhi Yuan4, Xijie Yu5, Frank Rauch6, Siobhan I Davis5, Shubin Zhang1, Hector Rios1, Marc K Drezner4, L Darryl Quarles3, Lynda F Bonewald1 & Kenneth E White51
Oral Biology, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA. 2
Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada. 3
Department of Internal Medicine, The Kidney Institute & Division of Nephrology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. 4
Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA. 5
Department of Medical & Molecular Genetics, Indiana University, Indianapolis, Indiana 46202, USA. 6
Shriners Hospital for Children, McGill University, Montreal, Quebec H3G 1A6, Canada. 7
These authors contributed equally to this work.
Correspondence should be addressed to L Darryl Quarles dquarles@kumc.edu or Leanne M Ward Lward@cheo.on.ca DMP1Dmp1FGF23DMP1The 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated. NEWS AND VIEWSBone talkNature Genetics News and Views (01 Nov 2006)
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