Partial rescue of PTH/PTHrP receptor knockout mice by targeted expression of the Jansen transgene.
Partial rescue of PTH/PTHrP receptor knockout mice by targeted expression of the Jansen transgene.
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DOI：
10.1210/endo.142.12.8553
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发表时间：
2001-12
期刊：
影响因子：
4.8
通讯作者：
D. W. Soegiarto;S. Kiachopoulos;E. Schipani;H. Jüppner;R. Erben;B. Lanske
中科院分区：
文献类型：
--
作者：
D. W. Soegiarto;S. Kiachopoulos;E. Schipani;H. Jüppner;R. Erben;B. Lanske
PTH/PTHrP受体(PPR(-/-))编码基因的纯合消融导致早期死亡和有限的发育缺陷，包括加速软骨细胞的分化。与纯合子PTHrP(PTHrP(-/-))动物的研究结果相反，这些PPR(-/-)小鼠的皮质骨增加，小梁骨减少，骨矿化缺陷。在Jansen的干骺端软骨发育不良症，一种由结构性活性PPR突变引起的疾病，以及在α1(I)型胶原启动子控制下表达这些受体突变之一(HKrk-H223R)的转基因动物中，出现了相反的观察结果。此外，在α1(II)型胶原启动子的控制下表达Jansen转基因可以延缓PTHrP(-/-)小鼠的软骨细胞分化，防止软骨细胞分化的急剧加速，从而挽救这些动物的早期死亡。在本研究中，我们证明了α1(II)型胶原启动子Jansen转基因恢复了PPR(-/-)小鼠的大部分骨异常，但不能阻止它们的围产期死亡。这些发现表明，除了胸腔异常导致的气体交换障碍外，其他因素也是导致PPR(-/-)小鼠过早死亡的原因之一。
The homozygous ablation of the gene encoding the PTH/PTHrP receptor (PPR(-/-)) leads to early lethality and limited developmental defects, including an acceleration of chondrocyte differentiation. In contrast to the findings in homozygous PTHrP-ablated (PTHrP(-/-)) animals, these PPR(-/-) mice show an increase in cortical bone, a decrease in trabecular bone, and a defect in bone mineralization. Opposite observations are made in Jansen's metaphyseal chondrodysplasia, a disorder caused by constitutively active PPR mutants, and in transgenic animals expressing one of these receptor mutants (HKrk-H223R) under control of the type alpha1(I) collagen promoter. Expression of the Jansen transgene under the control of the type alpha1(II) collagen promoter was, furthermore, shown to delay chondrocyte differentiation and to prevent the dramatic acceleration of chondrocyte differentiation in PTHrP(-/-) mice, thus rescuing the early lethality of these animals. In the present study we demonstrated that the type alpha1(II) collagen promoter Jansen transgene restored most of the bone abnormalities in PPR(-/-) mice, but did not prevent their perinatal lethality. These findings suggested that factors other than impaired gas exchange due to an abnormal rib cage contribute to the early death of PPR(-/-) mice.