Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice
Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice
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DOI：
10.1073/pnas.1110905108
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发表时间：
2011-11-15
影响因子：
11.1
通讯作者：
White, Kenneth E.
中科院分区：
文献类型：
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作者：
Farrow, Emily G.;Yu, Xijie;White, Kenneth E.
常染色体显性低磷血症性佝偻病（ADHR）在涉及成纤维细胞生长因子23（FGF 23）的疾病中是独特的，因为在FGF 23 176 RXXR 179/S180蛋白水解切割基序中具有R176 Q/W和R179 Q/W突变的个体可以从未受影响的状态循环到疾病延迟发作。这种发作可能发生在与缺铁相关的生理状态，包括青春期和妊娠期。为了测试铁状态在ADHR表型发展中的作用，将WT和R176 Q-Fgf 23敲入（ADHR）小鼠置于对照或低铁饮食。接受低铁饮食的WT和ADHR小鼠均具有显著升高的骨Fgf 23 mRNA。低铁饮食的WT小鼠维持正常的血清完整Fgf 23和磷酸盐代谢，血清C末端Fgf 23片段升高。相比之下，低铁饮食的ADHR小鼠具有升高的完整和C-末端Fgf 23，伴有低磷酸盐血症性骨软化。我们使用体外铁螯合分离铁缺乏对Fgf 23表达的影响。我们发现，铁螯合在体外导致Fgf 23 mRNA的显着增加，这是依赖于Mapk。因此，与FGF 23升高的其他综合征不同，我们的研究结果支持晚发性ADHR是基因-环境相互作用的产物的概念，其中FGF 23稳定突变和铁缺乏的组合存在可导致ADHR。
Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 176RXXR179/S180 proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.