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Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia

Year: 2008
Type: article
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.
DOI: 10.1172/jci32702
Authors: Baozhi Yuan, Masanori Takaiwa, Thomas L. Clemens, Jian Q. Feng, Rajiv Kumar, Peter S. Rowe, Yixia Xie, Marc K. Drezner
Institutions: University of Wisconsin–Madison, William S. Middleton Memorial Veterans Hospital, University of Alabama at Birmingham, University of Missouri–Kansas City, Mayo Clinic, University of Kansas
Language: English
Subfield: Nephrology
Field: Medicine
Open Access status: bronze
Funders: National Institutes of Health, U.S. Public Health Service, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, National Center for Research Resources
Awards: G1374147672, UAB Core Center for Basic Skeletal Research (CCBSR), G30277752, Biology of a Novel Phosphaturic Protein - sFRP-4, General Clinical Research Center, G3708310276, PATHOGENESIS OF VITAMIN D REFRACTORY DISEASES, Mentored Clinical Research Scholar Program Award, Hyperoxaluria and Nephrolithiasis After Gastric Bypass Surgery for Obesity, Oxygen Sensing and Osteogenesis, REGULATIOIN OF RENAL PHOSPHATE EXCRETION AND VITAMIN D METABOLISM BY FGF 7, G6717109241, Mineralization of the matrix in disease and health, G9000159662, G9000282168, G912487628, Mineralization and the Role of Matrixphosphoglycoprotein
OpenAlex ID: W2073327296
FWCI: 13.24
Cites: 49
Cited by: 182
Related to: 10