Aphysiological role and the controlmeellanism ofa phosphate senser

磷酸盐(PI)在骨矿化中起着重要的作用，细胞外磷酸盐的稳态维持主要是通过激素和磷酸盐敏感的感受器蛋白(II型Na/PI转运体)在近端肾小管重新吸收磷酸盐来实现的。遗传性低磷血症高钙尿症(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、软骨病和继发性高钙尿症为特征。最近，HHRH的连锁分析表明，候选基因是磷酸感受器(IIcNa/PI(napi-IIc)共转运体)。在目前的研究中，我们证明了HHRH时缺乏功能性的Napi-IIc蛋白会导致严重的肾脏PI消耗，导致低磷血症[10]。这些观察表明，Napi-IIc共转运体在肾脏PI重吸收和骨矿化中起重要作用，并可能是人体血浆PI浓度的关键决定因素(11)。然而，尚不清楚为什么不太丰富和能量不太有利的电中和转运体功能丧失会导致人类软骨病和软骨病，而更丰富的电生Napi-IIa转运体突变会导致轻微的骨骼表型，缺乏小鼠软骨病的典型特征。为了了解napi-IIa和napi-Ic转运体在整体维持PI动态平衡和骨矿化中的作用，我们中断了小鼠的napi-IIa/napi-Ic基因，并分析了每个突变体的表型。目前的研究表明，与小鼠相比，Napi-IIC可能是人类体内PI稳态的更重要的调节因子。

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.