title: Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia.
abstract: Patients with X-linked hypophosphatemia (XLH) and the hyp-mouse, a model of XLH characterized by a deletion in the Phex gene, manifest hypophosphatemia, renal phosphate wasting, and rickets/osteomalacia. Cloning of the PHEX/Phex gene and mutations in affected patients and hyp-mice established that alterations in PHEX/Phex expression underlie XLH. Although PHEX/Phex expression occurs primarily in osteoblast lineage cells, transgenic Phex expression in hyp-mouse osteoblasts fails to rescue the phenotype, suggesting that Phex expression at other sites underlies XLH. To establish whether abnormal Phex in osteoblasts and/or osteocytes alone generates the HYP phenotype, we created mice with a global Phex knockout (Cre-PhexDeltaflox/y mice) and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes (OC-Cre-PhexDeltaflox/y). Serum phosphorus levels in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in Cre-PhexDeltaflox/y and OC-Cre-PhexDeltaflox/y mice was associated with increased bone production and serum FGF-23 levels and decreased kidney membrane type IIa sodium phosphate cotransporter protein, as was the case in hyp-mice. In addition, Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice manifested comparable osteomalacia. These data provide evidence that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the hyp-mouse phenotype.
authors.affiliation: Department of Medicine, University of Wisconsin, GRECC, William F. Middleton Veterans Administration Hospital, Madison, Wisconsin, USA.
authors.forename: Baozhi
authors.initials: B
authors.lastname: Yuan
authors.forename: Masanori
authors.initials: M
authors.lastname: Takaiwa
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rowe
authors.forename: Yixia
authors.initials: Y
authors.lastname: Xie
authors.forename: Marc K
authors.initials: MK
authors.lastname: Drezner
mesh_terms: D000818:Animals; D001692:Biological Transport; D001842:Bone and Bones / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology*; D004195:Disease Models, Animal; D053098:Familial Hypophosphatemic Rickets / Q000201:enzymology*; D005269:Femur / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism; D040181:Genetic Diseases, X-Linked; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000201:enzymology*; D010011:Osteocytes / Q000201:enzymology*; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics / Q000502:physiology*; D010758:Phosphorus / Q000097:blood / Q000378:metabolism; D011859:Radiography; D014807:Vitamin D / Q000378:metabolism*
chemical_list: C000717428:Fgf23 protein, mouse; D014807:Vitamin D; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse