Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function
Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function
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DOI：
10.1007/s00774-007-0776-6
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发表时间：
2007-11-01
影响因子：
3.3
通讯作者：
Ozono, Keiichi
中科院分区：
文献类型：
--
作者：
Yamamoto, Takehisa;Michigami, Toshimi;Ozono, Keiichi
报告两例遗传性低磷血症性佝偻病伴高钙尿症（HHRH）的日本女性同胞。两人均表现为身材矮小、双腿弯曲，生化检查显示低磷酸盐血症、磷酸盐尿和高钙尿。血清1，25-二羟维生素D（1，25（OH）（2）D）浓度升高。在口服磷酸盐负荷试验中，HHRH患者血清磷酸盐水平明显升高，且升高幅度远高于X连锁低磷血症性佝偻病（XLH）患者，提示HHRH患者胃肠道对磷酸盐的吸收增加。骨组织学研究显示HHRH类骨质表面和宽度增加，这与骨软化症一致。在HHRH患者中，没有低矿化骨膜细胞病变，这是XLH在骨组织学中的标志。在其中一名HHRH患者中，单独使用磷酸盐几乎在一年内完全治愈了骨软化症，尽管药理剂量的1，25（OH）（2）D-3几乎没有效果。在从HHRH患者分离的成骨细胞中，生理浓度的1，25（OH）（2）D-3的基础碱性磷酸酶（ALP）活性和骨钙素合成不受增加的培养基磷酸盐浓度从0.5至4 mM的刺激。相比之下，这两个参数的刺激，增加中磷酸盐浓度在正常和XLH成骨细胞，虽然增加骨钙素合成的监管模式是不同的正常XLH成骨细胞; 2和4 mM的磷酸盐浓度至少是必要的正常和XLH成骨细胞，分别。磷酸盐转运蛋白基因分析发现磷酸盐转运蛋白NPT Ⅱ c型外显子中存在一个新的杂合突变（R564 C）。这些证据表明，在成骨细胞中磷酸盐的效用方面，HHRH中骨软化的发病机制与XLH不同。这些异常被推测与磷酸盐转运蛋白基因IIc型的异常功能有关，尽管这种磷酸盐转运蛋白在人类成骨细胞中的确切作用仍然未知。
Two cases of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) were reported in Japanese female siblings. Both of them manifested short stature and bowed legs, and biochemical examination revealed hypophosphatemia, phosphaturia, and hypercalciuria. The serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) were elevated. In the oral phosphate loading test, serum phosphate levels were markedly increased in the HHRH patients, and the elevation was much higher than that in patients affected with X-linked hypophosphatemic rickets (XLH), suggesting the increased gastrointestinal absorption of phosphate in HHRH. Bone histology studies showed increased osteoid surface and width in HHRH, which was compatible with osteomalacia. In the HHRH patients, there were no hypomineralized periosteocytic lesions, which was a hallmark of XLH in bone histology. In one of the HHRH patients, phosphate administration alone almost completely cured the osteomalacia within a year, although pharmacological doses of 1,25(OH)(2)D-3 had little effect. In osteoblasts isolated from a HHRH patient, basal alkaline phosphatase (ALP) activities and osteocalcin syntheses by a physiological concentration of 1,25(OH)(2)D-3 were not stimulated by the increased medium phosphate concentrations from 0.5 to 4mM. In contrast, these two parameters were stimulated by the increased medium phosphate concentrations both in normal and XLH osteoblasts, although the regulatory patterns of increased osteocalcin syntheses were different from normal to XLH osteoblasts; 2 and 4mM of phosphate concentrations at least were necessary for normal and XLH osteoblasts, respectively. The gene analysis of phosphate transporter revealed a novel heterozygous mutation (R564C) in the exon of phosphate transporter NPT type IIc. These lines of evidence suggested that the pathogenesis of osteomalacia in HHRH was different from XLH in terms of the utility of phosphate in osteoblasts. These abnormalities were speculated to be associated with the abnormal functions of phosphate transporter gene type IIc, although the exact roles of this phosphate transporter in the human osteoblast are still unknown.