Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia
Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia
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DOI：
10.1172/jci32702
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Drezner, Marc K.
中科院分区：
文献类型：
--
作者：
Yuan, Baozhi;Takaiwa, Masanori;Drezner, Marc K.
X连锁低磷血症患者和以PHEX基因缺失为特征的低磷小鼠模型，表现为低磷血症、肾脏磷酸盐消耗和软骨病。对PHEX/PHEX基因的克隆和在受影响的患者和Hyp小鼠中的突变证实了PHEX/PHEX表达的变化是XLH的基础。虽然PHEX/PHEX的表达主要发生在成骨细胞系细胞中，但转基因的PHEX在Hyp小鼠成骨细胞中的表达并不能挽救这种表型，这表明在其他位置的PHEX表达是XLH的基础。为了确定成骨细胞和/或骨细胞中的异常PHEX是否单独产生HYP表型，我们创建了全局PHEX基因敲除(CRE-PHEX(Delta Flox/y)小鼠)和成骨细胞和骨细胞中有条件的骨钙素促进(OC-Cre-PHEX(Delta Flox/y))PHEX失活的小鼠。CRE-PHEX(Delta FLOX/y)、OC-CRE-PHEX(Delta FLOX/y)和Hyp-小鼠的血清磷水平低于正常小鼠。CRE-Phe(Delta Flox/y)、OC-Cre-Phe(Delta Flox/y)和Hyp-小鼠的肾细胞膜磷酸盐转运与正常小鼠相比同样减少。CRE-PHEX(Delta Flox/y)和OC-CRE-PHEX(Delta Flox/y)小鼠的肾脏磷酸盐转运异常与骨量增加和血清成纤维细胞生长因子-23水平增加以及肾膜IIa型磷酸钠共转运蛋白降低有关，就像Hyp-小鼠一样。此外，CRE-PHEX(Delta Flox/y)、OC-Cre-PPhex(Delta Flox/y)和Hyp小鼠表现出类似的骨软化。这些数据提供的证据表明，仅成骨细胞和/或骨细胞中异常的PHEX功能就足以支持Hyp-小鼠的表型。
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-Phex(Delta flox/y) mice) and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes (OC-Cre-Phex(Delta flox/y)). Serum phosphorus levels in Cre-Phex(Delta flox/y), OC-Cre-Phex(Delta flox/y), and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in Cre-Phex(Delta flox/y), OC-Cre-Phex(Delta flox/y), and hyp-mice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in Cre-Phex(Delta flox/y) and OC-Cre-Phex(Delta flox/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-Phex(Delta flox/y), OC-Cre-PPhex(Delta flox/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.