Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice
Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice
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DOI：
10.1016/j.matbio.2004.09.007
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发表时间：
2004-11-01
期刊：
影响因子：
6.9
通讯作者：
Lanske, B
中科院分区：
文献类型：
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作者：
Sitara, D;Razzaque, MS;Lanske, B
成纤维细胞生长因子-23 (FGF-23) 是一种最近发现的分子，在常染色体显性低磷血症性佝偻病 (ADHR) 患者中发生突变，似乎参与磷酸盐稳态的调节。尽管在患有不同磷酸盐消耗性疾病（例如致癌性骨软化症 (OOM) 和 X 连锁低磷血症 (XLH)）的患者中检测到循环 FGF-23 水平升高，但尚不清楚 FGF-23 是否直接导致矿物质离子稳态调节异常以及骨发育。为了解决其中一些未解决的问题，我们生成了一个小鼠模型，其中整个 Fgf-23 基因被 lacZ 基因替换。 Fgf-23 null (Fgf-23(-/-)) 小鼠在第 17 天时表现出生长迟缓的迹象，出现严重的高磷酸盐血症，血清 1,25(OH)(2)D-3 水平升高，并在 13 周龄时死亡。组织学、分子和各种其他形态测量分析表明，Fgf-23(-/-) 小鼠的高磷酸盐血症伴有骨骼异常。 Fgf-23(-/-)小鼠全身骨矿物质含量(BMC)增加，但四肢骨矿物质密度(BMD)降低。总体而言，Fgf-23(-/-) 小鼠表现出矿化增加，但未矿化的类骨质积累导致明显的肢体畸形。此外，Fgf-23(-/-) 小鼠的软组织（包括心脏和肾脏）显示出过度矿化。为了进一步扩大我们对 Fgf-23 在磷酸盐稳态和骨骼矿化中作用的理解，我们将 Fgf-23(-/-) 动物与 Hyp 小鼠（相当于 XLH 的小鼠）杂交。有趣的是，缺乏两个 Fgf-23 等位基因的 Hip 雄性在血清磷酸盐水平和骨骼变化方面与 Fgf-23(-/-) 小鼠没有区别，这表明 Fgf-23 位于磷酸盐调节基因的上游，与 X 染色体 (Phex) 上的内肽酶同源，并且 Hip 小鼠（和 XLH 患者）血浆 Fgf-23 水平升高可能与至少对这种疾病中磷酸盐失衡负有部分责任。 (C) 2004 Elsevier B.V./国际基质生物学学会。版权所有。
Fibroblast growth factor-23 (FGF-23), a recently identified molecule that is mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR), appears to be involved in the regulation of phosphate homeostasis. Although increased levels of circulating FGF-23 were detected in patients with different phosphate-wasting disorders such as oncogenic osteomalacia (OOM) and X-linked hypophosphatemia (XLH), it is not yet clear whether FGF-23 is directly responsible for the abnormal regulation of mineral ion homeostasis and consequently bone development. To address some of these unresolved questions, we generated a mouse model, in which the entire Fgf-23 gene was replaced with the lacZ gene. Fgf-23 null (Fgf-23(-/-)) mice showed signs of growth retardation by day 17, developed severe hyperphosphatemia with elevated serum 1,25(OH)(2)D-3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23(-/-) mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and various other morphometric analyses. Fgf-23(-/-) mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs. Overall, Fgf-23(-/-) mice exhibited increased mineralization, but also accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23(-/-) mice showed excessive mineralization in soft tissues, including heart and kidney. To further expand our understanding regarding the role of Fgf-23 in phosphate homeostasis and skeletal mineralization, we crossed Fgf-23(-/-) animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hip males lacking both Fgf-23 alleles were indistinguishable from Fgf-23(-/-) mice, both in terms of serum phosphate levels and skeletal changes, suggesting that Fgf-23 is upstream of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (Phex) and that the increased plasma Fgf-23 levels in Hip mice (and in XLH patients) may be at least partially responsible for the phosphate imbalance in this disorder. (C) 2004 Elsevier B.V./International Society of Matrix Biology. All rights reserved.