PAPP-A2 expression by osteoblasts is required for normal postnatal growth in mice
PAPP-A2 expression by osteoblasts is required for normal postnatal growth in mice
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DOI：
10.1016/j.ghir.2015.09.003
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发表时间：
2015-12-01
影响因子：
1.4
通讯作者：
Christians, Julian K.
中科院分区：
文献类型：
--
作者：
Amiri, Neilab;Christians, Julian K.
目的：妊娠相关血浆蛋白-A2(PAPP-A2)是一种分解胰岛素样生长因子结合蛋白-5(IGFBP-5)的酶，IGFBP-5是骨中含量最丰富的IGFBP。Pappa2基因的缺失会减少小鼠的出生后生长和骨骼长度。本研究的目的是确定局部产生的PAPP-A2是否是正常骨生长所必需的。设计：我们通过在SP7(Osterix)启动子的控制下将条件性Pappa2缺失的小鼠与表达Cre重组酶的小鼠杂交，初步在成骨细胞中删除了Pappa2。通过测量3、6、10和12周龄的体质量和尾长以及12周龄的骨尺寸来检测破坏表达SP7的细胞中Pappa2的效果。结果：成骨细胞特异性Pappa2的缺失在各个年龄段都显著降低了体质量、尾长和线性骨尺寸。携带Cre转基因的条件性Pappa2缺失等位基因纯合子的小鼠比携带Cre转基因的对照组小，而与未携带转基因的小鼠比较，条件Pappa2缺失等位基因纯合子的小鼠并不比对照组小。这一结果明确地表明，表达SP7的细胞产生的PAPP-A2是正常生长所必需的。然而，在许多性状上，结构性Pappa2缺失比成骨细胞特异性Pappa2缺失的影响更大，这表明出生后的生长也受到其他来源的PAPP-A2的影响。免疫组织化学结果显示，PAPP-A2定位于骨痂、干骺端和成骨细胞，与骨生长有关。结论：局部产生的PAPP-A2是正常骨生长所必需的。(C)2015爱思唯尔有限公司。保留所有权利。
Objective: Pregnancy associated plasma protein-A2 (PAPP-A2) is a protease that cleaves insulin-like growth factor binding protein-5 (IGFBP-5), the most abundant IGFBP in bone. Deletion of Pappa2 reduces postnatal growth and bone length in mice. The aim of this study was to determine whether locally produced PAPP-A2 is required for normal bone growth.Design: We deleted Pappa2 primarily in osteoblasts by crossing conditional Pappa2 deletion mice with mice expressing Cre recombinase under the control of the Sp7 (Osterix) promoter. Effects of disrupting Pappa2 in Sp7-expressing cells were examined by measuring body mass and tail length at 3, 6, 10 and 12 weeks of age and bone dimensions at 12 weeks.Results: Body mass, tail length, and linear bone dimensions were significantly reduced at all ages by osteoblastspecific Pappa2 deletion. Mice homozygous for the conditional Pappa2 deletion allele and carrying the Cre transgene were smaller than controls carrying the Cre transgene, whereas mice homozygous for the conditional Pappa2 deletion allele were not smaller than controls when comparing mice not carrying the transgene. This result unambiguously demonstrates that PAPP-A2 produced by Sp7 expressing cells is required for normal growth. However, constitutive Pappa2 deletion had greater effects than osteoblast-specific Pappa2 deletion for many traits, indicating that post-natal growth is also affected by other sources of PAPP-A2. Immunohistochemistry revealed that PAPP-A2 localized in the epiphysis and metaphysis as well as osteoblasts, consistent with a role in bone growth.Conclusion: Locally-produced PAPP-A2 is required for normal bone growth. (C) 2015 Elsevier Ltd. All rights reserved.