Pathogenic role of Fgf23 in Hyp mice
Pathogenic role of Fgf23 in Hyp mice
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DOI：
10.1152/ajpendo.00008.2006
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发表时间：
2006-07-01
影响因子：
5.1
通讯作者：
Quarles, L. Darryl
中科院分区：
文献类型：
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作者：
Liu, Shiguang;Zhou, Jianping;Quarles, L. Darryl
PHEX（与X染色体上的内肽酶具有同源性的磷酸盐调节基因）内肽酶（X连锁低磷酸盐血症（XLH）中的致病基因）的失活突变导致成纤维细胞生长因子-23（FGF 23）（一种骨源性磷酸盐尿因子）的循环水平增加。为了确定FGF 23在XLH中的因果作用，我们产生了组合的Fgf 23缺陷型增强型绿色荧光蛋白（eGFP）报告基因和Phex缺陷型Hyp小鼠模型（Fgf 23（+/-）IHyp）。eGFP表达在包埋在骨中的骨细胞中表达，这些骨细胞表现出响应于Phex缺乏的eGFP的显著上调，并且在骨髓小静脉中的CD 31阳性细胞中表达低水平的eGFP，而与Phex无关。在来源于Fgf 23（+/-）IHyp小鼠的骨髓基质细胞（BMSC）中，eGFP表达也在矿化结节内的骨细胞样细胞中选择性增加，并在CD 31阳性细胞中检测到低水平。令人惊讶的是，eGFP表达在细胞表面成骨细胞中没有增加，表明Phex缺乏是必要的，但不足以增加成骨细胞谱系中的Fgf 23表达。与骨细胞分化和/或细胞外基质相关的其他因子是Phex缺乏刺激骨中Fgf 23基因转录所必需的。无论如何，Hyp小鼠Fgf 23的缺失逆转了与Phex缺乏相关的低磷酸盐血症、异常1，25（OH）（2）D-3水平、佝偻病和骨软化症。这些结果表明，Fgf 23作用于Phex下游，导致Hyp小鼠的肾和骨表型。
Inactivating mutations of the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) endopeptidase, the disease-causing gene in X-linked hypophosphatemia (XLH), results in increased circulating levels of fibroblastic growth factor-23 (FGF23), a bone-derived phosphaturic factor. To determine the causal role of FGF23 in XLH, we generated a combined Fgf23-deficient enhanced green fluorescent protein (eGFP) reporter and Phex-deficient Hyp mouse model (Fgf23(+/-)IHyp). eGFP expression was expressed in osteocytes embedded in bone that exhibited marked upregulation of eGFP in response to Phex deficiency and in CD31-positive cells in bone marrow venules that expressed low eGFP levels independently of Phex. In bone marrow stromal cells (BMSCs) derived from Fgf23(+/-)IHyp mice, eGFP expression was also selectively increased in osteocyte-like cells within mineralization nodules and detected in low levels in CD31-positive cells. Surprisingly, eGFP expression was not increased in cell surface osteoblasts, indicating that Phex deficiency is necessary but not sufficient for increased Fgf23 expression in the osteoblast lineage. Additional factors, associated with either osteocyte differentiation and/or extracellular matrix, are necessary for Phex deficiency to stimulate Fgf23 gene transcription in bone. Regardless, the deletion of Fgf23 from Hyp mice reversed the hypophosphatemia, abnormal 1,25(OH)(2)D-3 levels, rickets, and osteomalacia associated with Phex deficiency. These results suggest that Fgf23 acts downstream of Phex to cause both the renal and bone phenotypes in Hyp mice.