Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation.
Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation.
复制标题
DOI：
10.1172/jci19504
复制
发表时间：
2003-11
期刊：
影响因子：
--
通讯作者：
J. Vanhouten;P. Dann;A. F. Stewart;C. Watson;M. Pollak;A. Karaplis;J. Wysolmerski
中科院分区：
文献类型：
--
作者：
J. Vanhouten;P. Dann;A. F. Stewart;C. Watson;M. Pollak;A. Karaplis;J. Wysolmerski
大量的钙通过牛奶传递给后代。这种需求导致哺乳期母亲的负钙平衡，并与快速骨质流失有关。哺乳期骨丢失的机制仅部分了解。一些研究表明，甲状旁腺相关蛋白（PTHrP）可能分泌到泌乳期乳腺循环和调节哺乳期骨转换。由于乳腺发育失败，在PTHrP的情况下，传统的PTHrP敲除小鼠不能用于解决这种可能性。为了检验这一假设，我们因此使用了携带β-乳球蛋白启动子驱动的Cre转基因、一个无效PTHrP等位基因和一个floxed PTHrP等位基因的小鼠。Cre在妊娠晚期和哺乳期乳腺上皮细胞中特异性表达导致PTHrP基因的有效缺失;乳腺PTHrP mRNA和乳汁PTHrP蛋白几乎完全缺失。从泌乳乳腺中去除PTHrP导致循环PTHrP和1，25-二羟基维生素D和尿cAMP水平降低。此外，骨转换减少，泌乳期骨丢失减弱。我们的结论是，在哺乳期乳腺上皮细胞是循环PTHrP的来源，促进骨丢失的骨吸收率增加。
Large amounts of calcium are transferred to offspring by milk. This demand results in negative calcium balance in lactating mothers and is associated with rapid bone loss. The mechanisms of bone loss during lactation are only partly understood. Several studies have suggested that parathyroid hormone-related protein (PTHrP) might be secreted into the circulation by the lactating mammary gland and regulate bone turnover during lactation. Because mammary development fails in the absence of PTHrP, conventional PTHrP knockout mice cannot be used to address this possibility. To examine this hypothesis, we therefore used mice carrying a beta-lactoglobulin promoter-driven Cre transgene, one null PTHrP allele, and one floxed PTHrP allele. Expression of Cre specifically in mammary epithelial cells during late pregnancy and lactation resulted in efficient deletion of the PTHrP gene; mammary gland PTHrP mRNA and milk PTHrP protein were almost completely absent. Removal of PTHrP from the lactating mammary glands resulted in reductions in levels of circulating PTHrP and 1,25-dihydroxy vitamin D and urinary cAMP. In addition, bone turnover was reduced and bone loss during lactation was attenuated. We conclude that during lactation mammary epithelial cells are a source of circulating PTHrP that promotes bone loss by increasing rates of bone resorption.