Aphysiological role and the controlmeellanism ofa phosphate senser

磷酸盐（Pi）在骨矿化过程中起重要作用，细胞外磷酸盐的稳态维持主要通过近端肾小管对磷酸盐的重吸收来实现，这种重吸收是通过激素和磷酸盐敏感的传感蛋白（II型Na/Pi转运蛋白）来实现的。遗传性低磷血症性佝偻病伴高钙尿症（HHRH）是一种罕见的常染色体隐性遗传性疾病，以低磷血症、身材矮小、佝偻病和/或骨软化及继发性吸收性高钙尿症为特征。最近，HHRH的连锁分析表明，候选基因是磷酸盐传感器（IIc型Na/Pi（NaPi-IIc）协同转运蛋白）。在本研究中，我们证明了HHRH缺乏功能性NaPi-IIc蛋白会导致严重的肾Pi消耗，导致低磷酸盐血症（10）。这些观察结果表明，NaPi-IIc协同转运蛋白在肾Pi重吸收和骨矿化中具有重要作用，并且可能是人体血浆Pi浓度的关键决定因素（11）。然而，目前尚不清楚为什么不太丰富和能量不太有利的电中性NaPi-Iia转运蛋白的功能丧失会导致人类佝偻病和骨软化症，而更丰富的产电NaPi-Iia转运蛋白的突变会导致小鼠缺乏佝偻病和骨软化症的典型特征的轻度骨骼表型。为了了解NaPi-Iia和NaPi-Iic转运蛋白在Pi稳态和骨矿化的整体维持中的作用，我们破坏了小鼠NaPi-Iia/NaPi-Iic基因，并分析了每个突变体的表型。目前的研究表明，NaPi-Iic可能是一个更重要的调节Pi稳态在人类比小鼠。

Phosphate (Pi) has long been recognized to play an important role in bone mineralization.The homeostatic maintenance of extracellular phosphate is achieved primarily by re-absorption of phosphate in the proximal kidney tubule through the hormone- and phosphate sensitive sensor protein (type II Na/Pi cotrnsporter. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare inherited disorder in an autosomal recessive fashion, characterized by hypophosphatemia, short stature, rickets and/or osteomalacia and secondary absorptive hypercalciuria. More recently, linkage analysis of HHRH demonstrated that the candidate gene is the phosphate sensor (type IIc Na/Pi (NaPi-IIc) cotransporter). In the present study, we demonstrated that lack of functional NaPi-IIc protein with HHRH results in severe renal Pi-wasting, leading to hypophosphatemia (10). These observations suggest that the NaPi-IIc cotransporter has an important role in renal Pi reabsorption and bone mineralization, and may be a key determinant of plasma Pi concentrations in human (11). However, it is not clear why loss of function of the less abundant and energetically less favorable electroneutral NaPi-Iic transporter causes rickets and osteomalacia in humans whereas mutations in the more abundant electrogenic NaPi-Iia transporter elicits a mild skeletal phenotype that lacks the typical features of rickets and osteomalacia in mice. To understand the role of NaPi-Iia and NaPi-Iic transporters in the overall maintenance of Pi homeostasis and bone mineralization, we have disrupted the murine NaPi-Iia/NaPi-Iic gene and analyzed phenotypes of each mutant. The present studies suggest that NaPi-Iic may be a more important regulator of Pi homeostasis in humans than in mice.