Deletion of PTH rescues skeletal abnormalities and high osteopontin levels in Klotho-/- mice.
Deletion of PTH rescues skeletal abnormalities and high osteopontin levels in Klotho-/- mice.
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DOI：
10.1371/journal.pgen.1002726
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Lanske B
中科院分区：
文献类型：
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作者：
Yuan Q;Sato T;Densmore M;Saito H;Schüler C;Erben RG;Lanske B
正常矿物质离子稳态的维持对于许多生物活动至关重要，包括骨骼的适当矿化。甲状旁腺激素（PTH）、Klotho和FGF 23已被证明通过复杂的反馈机制作为血清钙和磷酸盐稳态的关键调节剂。Fgf 23 −/−和Klotho−/−（Kl−/−）小鼠的表型非常相似，包括高钙血症、高磷血症、维生素D过多症、PTH水平抑制和严重骨软化症/类骨质增生症。我们最近报道，从Fgf 23 −/−小鼠中完全消除PTH通过抑制血清维生素D和钙水平改善了Fgf 23 −/−/PTH−/−小鼠的表型。然而，Fgf 23 −/−小鼠的严重骨软化持续存在，表明不同的机制是导致这种矿化缺陷的原因。在目前的研究中，我们证明了从Kl−/−（Kl−/−/PTH−/−或DKO）小鼠中缺失PTH可以纠正异常的骨骼表型。骨转换标志物恢复到野生型水平;更重要的是，在Kl−/−/PTH−/−小鼠中，骨骼矿化缺陷得到完全挽救。有趣的是，骨软化症的纠正伴随着骨和血清中高水平骨桥蛋白（Opn）的降低。在Fgf 23 −/−/PTH−/−小鼠中未观察到Opn水平的这种降低，这些小鼠表现出持续的骨软化。这一重要的体内发现得到了使用颅骨成骨细胞培养物的体外研究的证实，这些培养物显示了正常化的Opn表达和Kl−/−/PTH−/−小鼠中的获救矿化。此外，Kl−/−小鼠的持续PTH输注显著增加了Opn水平和类骨质体积，并降低了骨小梁体积。总之，我们的研究结果首次表明，PTH直接影响Kl−/−小鼠的矿化障碍和骨骼畸形，但不影响Fgf 23 −/−小鼠，可能是通过调节Opn表达。这些是对PTH在骨骼和疾病过程中的作用的重要新认识，并表明PTH与Klotho的FGF 23独立相互作用。正常矿物质离子稳态的维持对于许多生物活动至关重要，包括骨骼的适当矿化。PTH、Klotho和FGF 23是血液矿物质离子稳态的关键调节剂。Klotho是一种I型膜蛋白，已被鉴定为FGF 23结合和激活其受体所需的辅因子。Klotho或Fgf 23活性的丧失导致类似的异常表型，包括骨骼矿化的严重缺陷和矿物离子平衡的改变。在这里，我们描述了一种新的小鼠模型，在该模型中，我们从Kl−/−小鼠中消除了PTH，我们可以证明，在Kl−/−/PTH−/−小鼠中，骨骼矿化缺陷被完全挽救，并且这种现象伴随着骨骼和血清中高水平骨桥蛋白的减少。我们还提供了额外的数据，表明持续输注Kl−/−小鼠PTH导致Opn水平升高，随后增加类骨质体积。有趣的是，这一结果与我们之前的报告不同，我们在报告中描述了Fgf 23 −/−/PTH−/−小鼠的骨软化和高Opn水平持续存在。我们的研究结果表明，PTH，可能通过调节骨桥蛋白，是负责骨骼矿化缺陷的Kl−/−小鼠，但不是在Fgf 23 −/−小鼠。
Maintenance of normal mineral ion homeostasis is crucial for many biological activities, including proper mineralization of the skeleton. Parathyroid hormone (PTH), Klotho, and FGF23 have been shown to act as key regulators of serum calcium and phosphate homeostasis through a complex feedback mechanism. The phenotypes of Fgf23−/− and Klotho−/− (Kl−/−) mice are very similar and include hypercalcemia, hyperphosphatemia, hypervitaminosis D, suppressed PTH levels, and severe osteomalacia/osteoidosis. We recently reported that complete ablation of PTH from Fgf23−/− mice ameliorated the phenotype in Fgf23−/−/PTH−/− mice by suppressing serum vitamin D and calcium levels. The severe osteomalacia in Fgf23−/− mice, however, persisted, suggesting that a different mechanism is responsible for this mineralization defect. In the current study, we demonstrate that deletion of PTH from Kl−/− (Kl−/−/PTH−/− or DKO) mice corrects the abnormal skeletal phenotype. Bone turnover markers are restored to wild-type levels; and, more importantly, the skeletal mineralization defect is completely rescued in Kl−/−/PTH−/− mice. Interestingly, the correction of the osteomalacia is accompanied by a reduction in the high levels of osteopontin (Opn) in bone and serum. Such a reduction in Opn levels could not be observed in Fgf23−/−/PTH−/− mice, and these mice showed sustained osteomalacia. This significant in vivo finding is corroborated by in vitro studies using calvarial osteoblast cultures that show normalized Opn expression and rescued mineralization in Kl−/−/PTH−/− mice. Moreover, continuous PTH infusion of Kl−/− mice significantly increased Opn levels and osteoid volume, and decreased trabecular bone volume. In summary, our results demonstrate for the first time that PTH directly impacts the mineralization disorders and skeletal deformities of Kl−/−, but not of Fgf23−/− mice, possibly by regulating Opn expression. These are significant new perceptions into the role of PTH in skeletal and disease processes and suggest FGF23-independent interactions of PTH with Klotho. Maintenance of normal mineral ion homeostasis is crucial for many biological activities, including proper mineralization of the skeleton. PTH, Klotho, and FGF23 are the key regulators of blood mineral ion homeostasis. Klotho is a type-I membrane protein and has been identified as cofactor required for FGF23 to bind and activate its receptor. Loss of either Klotho or Fgf23 activity results in a similar abnormal phenotype, including severe defects in skeletal mineralization and alterations in mineral ion balance. Here we describe a new mouse model in which we eliminated PTH from Kl−/− mice, and we can show that the skeletal mineralization defect was completely rescued in Kl−/−/PTH−/− mice and that this phenomenon was accompanied by a reduction in the high levels of osteopontin in bone and serum. We also present additional data showing that continuous infusion of Kl−/− mice with PTH results in an elevation in Opn levels and subsequently increased osteoid volume. Interestingly, this result differs from our previous report in which we describe that the osteomalacia and the high Opn levels in Fgf23−/−/PTH−/− mice persisted. Our finding suggests that PTH, possibly by regulating osteopontin, is responsible for the skeletal mineralization defect in Kl−/− mice, but not in Fgf23−/− mice.
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影响因子：
6.2
作者：
Julien, Marion;Khoshniat, Solmaz;Guicheux, Jerome
通讯作者：
Guicheux, Jerome
影响因子：
4.8
作者：
Miao, DS;He, B;Karaplis, AC
通讯作者：
Karaplis, AC
DOI：
10.1006/bbrc.1997.8019
发表时间：
1998-01-26
影响因子：
3.1
作者：
Matsumura, Y;Aizawa, H;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
4.8
作者：
Brownstein, Catherine A.;Zhang, Junhui;Carpenter, Thomas O.
通讯作者：
Carpenter, Thomas O.
DOI：
10.1038/nrendo.2009.196
发表时间：
2009-11
期刊：
Nature reviews. Endocrinology
影响因子：
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作者：
通讯作者：
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