Increased Bone Volume and Correction of HYP Mouse Hypophosphatemia in the Klotho/HYP Mouse
Increased Bone Volume and Correction of HYP Mouse Hypophosphatemia in the Klotho/HYP Mouse
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DOI：
10.1210/en.2009-0564
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发表时间：
2010-02-01
期刊：
影响因子：
4.8
通讯作者：
Carpenter, Thomas O.
中科院分区：
文献类型：
--
作者：
Brownstein, Catherine A.;Zhang, Junhui;Carpenter, Thomas O.
PHEX的失活突变导致x连锁低磷血症，并导致循环成纤维细胞生长因子23 （FGF23）增加。FGF23的作用依赖于Klotho，它将FGF受体1转化为FGF23特异性受体。Klotho的破坏导致复杂的骨表型和高磷血症，这是x连锁低磷血症的相反表型。我们通过创建双敲除（Klotho/HYP）小鼠来检测破坏Klotho和PHEX的效果。联合破坏纠正了HYP小鼠的低磷血症，表明Klotho对PHEX具有上位性。在除野生型外的所有组中，FGF23水平均升高，表明Klotho是FGF23依赖性磷酸化活性所必需的。在HYP小鼠中降低的1,25-二羟基维生素D水平在Klotho和Klotho/HYP小鼠中相对升高，表明Klotho对FGF23对维生素D代谢的影响是必要的。Klotho和Klotho/HYPmice的血清PTH水平均降低。此外，Klotho/HYP中Klotho null表型持续存在，维持了Klotho null小鼠的瘦弱表型和寿命下降。值得注意的是，微计算机断层扫描分析显示，Klotho/HYP小鼠的骨小梁体积分数高于其他所有组（Klotho/HYP, 56.2 +/- 6.3%; Klotho, 32.5 +/- 10.3%； HYP, 8.6 +/- 7.7%；野生型，21.4 +/- 3.4%,P < 0.004）。组织形态计量学分析证实，Klotho/HYP小鼠的骨小梁密度明显增加，HYP小鼠的类骨体积明显增加。这些观察结果表明，随着Klotho功能丧失，HYP小鼠通常产生的过量类骨（但不能矿化）在双敲除中产生和矿化，导致小梁骨密度显著增强。（中国医学杂志）
Inactivating mutations of PHEX cause X-linked hypophosphatemia and result in increased circulating fibroblast growth factor 23 (FGF23). FGF23 action is dependent upon Klotho, which converts FGF receptor 1 into an FGF23-specific receptor. Disruption of Klotho results in a complex bone phenotype and hyperphosphatemia, the converse phenotype of X-linked hypophosphatemia. We examined effects of disrupting both Klotho and PHEX by creating a double-knockout (Klotho/HYP) mouse. The combined disruption corrected the hypophosphatemia in HYP mice, indicating that Klotho is epistatic to PHEX. FGF23 levels remained elevated in all groups except wild-type, indicating that Klotho is necessary for FGF23-dependent phosphaturic activity. 1,25-DihydroxyvitaminDlevels, reduced in HYP mice, were comparably elevated in Klotho and Klotho/HYP mice, demonstrating that Klotho is necessary for FGF23's effect on vitamin D metabolism. Serum PTH levels were reduced in both Klotho and Klotho/HYPmice. Moreover, the Klotho null phenotype persisted in Klotho/HYP, maintaining the runty phenotype and decreased life span of Klotho null mice. Notably, microcomputed tomography analysis demonstrated greater trabecular bone volume fraction in Klotho/HYP mice than that in all other groups (Klotho/HYP, 56.2 +/- 6.3%; Klotho, 32.5 +/- 10.3%; HYP, 8.6 +/- 7.7%; and wild type, 21.4 +/- 3.4%; P < 0.004). Histomorphometric analysis confirmed the markedly increased trabecular bone density in Klotho/HYP mice and the well-established increase in osteoid volume in HYP mice. These observations suggest that with addition of Klotho loss of function, the overabundant osteoid typically produced in HYP mice (but fails to mineralize) is produced and mineralized in the double knockout, resulting in markedly enhanced trabecular bone density. (Endocrinology 151: 492-501, 2010)