Genetic evidence of serum phosphate-independent functions of FGF-23 on bone.
Genetic evidence of serum phosphate-independent functions of FGF-23 on bone.
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DOI：
10.1371/journal.pgen.1000154
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发表时间：
2008-08-08
期刊：
影响因子：
4.5
通讯作者：
Lanske B
中科院分区：
文献类型：
--
作者：
Sitara D;Kim S;Razzaque MS;Bergwitz C;Taguchi T;Schüler C;Erben RG;Lanske B
维持生理磷酸盐平衡具有至关重要的生物学意义，因为它是细胞功能、能量代谢和骨骼矿化的基础。成纤维细胞生长因子-23（FGF-23）是磷酸盐稳态的主要调节因子，但这种调节的分子机制尚未完全了解。在小鼠（Fgf-23−/−）中靶向破坏Fgf-23基因可导致高磷酸盐血症，并增加肾钠/磷酸盐协同转运蛋白2a（NaPi 2a）蛋白丰度。为了阐明NaPi 2a在Fgf-23−/−小鼠中肾近端小管表达增强的病理生理学作用，并检查Fgf-23在骨中的血清磷酸盐非依赖性功能，我们产生了一种新的Fgf-23和NaPi 2a基因缺陷的小鼠品系，并确定了从Fgf-23−/−小鼠中去除NaPi 2a对磷酸盐稳态和骨骼矿化的影响。与Fgf-23−/−动物相比，Fgf-23−/−/NaPi 2a −/−双突变小鼠存活并表现出正常的体力活动。生化分析显示，从Fgf-23−/−小鼠中去除NaPi 2a可在6周龄时将高磷酸盐血症逆转为低磷酸盐血症。令人惊讶的是，尽管Fgf-23−/−/NaPi 2a −/−的血清磷酸盐水平完全逆转，但它们的骨骼表型仍然类似于Fgf-23 −/−动物。这项研究的结果提供了NaPi 2a在调节Fgf-23−/−小鼠异常磷酸盐稳态中的体内病理作用的第一个遗传证据，即在同一动物中缺失NaPi 2a和Fgf-23基因。双突变体的骨骼异常的持久性表明，FGF-23影响骨矿化独立的系统磷酸盐稳态。最后，我们的数据支持（1）磷酸盐稳态的调节是FGF-23的全身作用，而（2）骨骼矿化和软骨细胞分化似乎是FGF-23的作用，不依赖于磷酸盐稳态。磷酸盐稳态的调节是一个涉及肠、肾和骨的严格控制的激素过程，这种稳态的不平衡可能影响整体矿化。成纤维细胞生长因子-23（FGF-23）是在骨中产生的循环激素，其主要靶向肾脏以控制钠/磷酸盐共转运蛋白NaPi 2a和NaPi 2c的活性。这些转运蛋白负责将磷酸盐离子主动重吸收到体内，以维持生理血清磷酸盐水平。FGF-23活性的变化导致与磷酸盐消耗或保留相关的人类疾病。Fgf-23活性丧失的基因改变小鼠表现出严重的高磷酸盐血症，伴随着NaPi 2a活性的增加，并且它们发生异常的骨矿化。在这里，我们描述了一种新的小鼠模型，在该模型中，我们消除了NaPi 2a从Fgf-23裸小鼠，并显示高磷酸盐血症逆转为低磷酸盐血症，表明NaPi 2a是磷酸盐稳态的主要调节剂。然而，在缺乏FGF-23功能的小鼠中观察到的骨骼矿化缺陷在这些小鼠中不存在NaPi 2a时保持不变。因此，我们的数据表明，FGF-23在控制骨矿化的作用独立于全身磷酸盐水平。
Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23−/−) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23−/− mice and to examine serum phosphate–independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23−/− mice on phosphate homeostasis and skeletal mineralization. Fgf-23−/−/NaPi2a−/− double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23−/− animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23−/− mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23−/−/NaPi2a−/−, their skeletal phenotype still resembles the one of Fgf23−/− animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23−/− mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis. Regulation of phosphate homeostasis is a tightly controlled hormonal process involving the intestine, kidneys, and bone, and imbalance of this homeostasis may influence overall mineralization. Fibroblast growth factor-23 (FGF-23) is a circulating hormone produced in the bone that mainly targets the kidneys to control the activity of the sodium/phosphate co-transporters NaPi2a and NaPi2c. These transporters are responsible for actively reabsorbing phosphate ions into the body to maintain physiological serum phosphate levels. Changes in FGF-23 activity lead to human disorders associated with either phosphate wasting or retention. Genetically altered mice in which Fgf-23 activity is lost exhibit severe hyperphosphatemia accompanied by increased NaPi2a activity, and they develop abnormal bone mineralization. Here we describe a new mouse model in which we eliminated NaPi2a from Fgf-23 null mice and show reversal of hyperphosphatemia to hypophosphatemia, suggesting that NaPi2a is the major regulator of phosphate homeostasis. However, the skeletal mineralization defect observed in mice lacking Fgf-23 function remained unchanged in the absence of NaPi2a in these mice. Thus our data indicate that Fgf-23 has a role in controlling bone mineralization independent of systemic phosphate levels.
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DOI：
10.1007/bf02023080
发表时间：
1990-12-01
期刊：
ZEITSCHRIFT FUR ERNAHRUNGSWISSENSCHAFT
影响因子：
--
作者：
ERBEN, RG;KOHN, B;RAMBECK, WA
通讯作者：
RAMBECK, WA
影响因子：
30.8
作者：
Lorenz-Depiereux, Bettina;Bastepe, Murat;Strom, Tim M.
通讯作者：
Strom, Tim M.
DOI：
10.1073/pnas.0704446104
发表时间：
2007-06-26
影响因子：
11.1
作者：
Berndt, Theresa;Thomas, Leslie F.;Kumar, Rajiv
通讯作者：
Kumar, Rajiv
影响因子：
5.3
作者：
Goetz, Regina;Beenken, Andrew;Mohammadi, Moosa
通讯作者：
Mohammadi, Moosa
DOI：
10.1073/pnas.95.9.5372
发表时间：
1998-04-28
影响因子：
11.1
作者：
Beck, L;Karaplis, AC;Tenenhouse, HS
通讯作者：
Tenenhouse, HS