title: 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.affiliation: Oral Biology, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Ward
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Lu
authors.forename: Yixia
authors.initials: Y
authors.lastname: Xie
authors.forename: Baozhi
authors.initials: B
authors.lastname: Yuan
authors.forename: Xijie
authors.initials: X
authors.lastname: Yu
authors.forename: Frank
authors.initials: F
authors.lastname: Rauch
authors.forename: Siobhan I
authors.initials: SI
authors.lastname: Davis
authors.forename: Shubin
authors.initials: S
authors.lastname: Zhang
authors.forename: Hector
authors.initials: H
authors.lastname: Rios
authors.forename: Marc K
authors.initials: MK
authors.lastname: Drezner
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
authors.forename: Lynda F
authors.initials: LF
authors.lastname: Bonewald
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: White
mesh_terms: D000328:Adult; D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D002113:Calcification, Physiologic / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008903:Minerals / Q000378:metabolism*; D010011:Osteocytes / Q000473:pathology / Q000502:physiology*; D010018:Osteomalacia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D010710:Phosphates / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D012279:Rickets / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D008903:Minerals; D010710:Phosphates; D010750:Phosphoproteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23