Updated in 12/4/2008 6:31:44 PM      Viewed: 231 times      (Journal Article)
Nat Genet 38 (11): 1310-5 (2006)

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

J Q Feng , L M Ward , S Liu , Y Lu , Y Xie , B Yuan , X Yu , F Rauch , S I Davis , S Zhang , H Rios , M K Drezner , L D Quarles , L F Bonewald , K E White
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.
ISSN: 1061-4036 (Print)     
Notes
NovLoss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism