Aphysiological role and the controlmeellanism ofa phosphate senser

磷酸盐 (Pi) 长期以来被认为在骨矿化中发挥重要作用。细胞外磷酸盐的稳态维持主要是通过激素和磷酸盐敏感传感器蛋白（II 型 Na/Pi 协同转运蛋白）在近端肾小管中重吸收磷酸盐来实现。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，其特征为低磷血症、身材矮小、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 HHRH 缺乏功能性 NaPi-IIc 蛋白会导致严重的肾 Pi 消耗，从而导致低磷血症 (10)。 NaPi-Iic 转运蛋白在肾 Pi 重吸收和骨矿化中发挥着重要作用，可能是人类血浆 Pi 浓度的关键决定因素 (11)。然而，尚不清楚为何较少丰富且能量中性较差的 NaPi-Iic 转运蛋白的功能丧失会导致人类佝偻病和骨软化症，而较丰富的电 NaPi-Iia 转运蛋白的突变会引发缺乏佝偻病和骨软化症典型特征的轻度骨骼表型。为了了解 NaPi-Iia 和 NaPi-Iic 转运蛋白在维持 Pi 稳态和骨矿化中的作用，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 可能是人类比小鼠更重要的 Pi 稳态调节剂。

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.