Department of Ob/Gyn., Stanford University School of Medicine, Stanford, CA, USA.
Biol Reprod. 2010 Jun;82(6):1129-38. doi: 10.1095/biolreprod.109.079517. Epub 2010 Feb 3.
The insulin-like growth factor (IGF) system plays an important role in regulating ovarian follicular development and steroidogenesis. IGF binding proteins (IGFBP) mostly inhibit IGF actions, and IGFBP proteolysis is a major mechanism for regulating IGF bioavailability. Pregnancy-associated plasma protein-A (PAPPA) is a secreted metalloprotease responsible for cleavage of IGFBP4 in the ovary. The aim of this study was to investigate whether PAPPA plays a role in regulating ovarian functions and female fertility by comparing the reproductive phenotype of wild-type (WT) mice with mice heterozygous or homozygous for a targeted Pappa gene deletion (heterozygous and PAPP-A knockout [KO] mice, respectively). When mated with WT males, PAPP-A KO females demonstrated an overall reduction in average litter size. PAPP-A KO mice had a reduced number of ovulated oocytes, lower serum estradiol levels following equine chorionic gonadotropin administration, lower serum progesterone levels after human chorionic gonadotropin injection, and reduced expression of ovarian steroidogenic enzyme genes, compared to WT controls. In PAPP-A KO mice, inhibitory IGFBP2, IGFBP3, and IGFBP4 ovarian gene expression was reduced postgonadotropin stimulation, suggesting some compensation within the ovarian IGF system. Expression levels of follicle-stimulating hormone receptor, luteinizing hormone receptor, and genes required for cumulus expansion were not affected. Analysis of preovulatory follicular fluid showed complete loss of IGFBP4 proteolytic activity in PAPP-A KO mice, demonstrating no compensation for loss of PAPPA proteolytic activity by other IGFBP proteases in vivo in the mouse ovary. Taken together, these data demonstrate an important role of PAPPA in modulating ovarian function and female fertility by control of the bioavailability of ovarian IGF.
胰岛素样生长因子（IGF）系统在调节卵巢卵泡发育和类固醇生成中起着重要作用。IGF 结合蛋白（IGFBP）主要抑制 IGF 作用，而 IGFBP 蛋白水解是调节 IGF 生物利用度的主要机制。妊娠相关血浆蛋白-A（PAPPA）是一种分泌型金属蛋白酶，负责在卵巢中切割 IGFBP4。本研究旨在通过比较野生型（WT）小鼠与杂合或纯合靶向 Pappa 基因缺失（杂合和 PAPPA-A 敲除[KO]小鼠）的小鼠的生殖表型，研究 PAPPA 是否通过调节卵巢功能和雌性生育能力发挥作用。与 WT 雄性交配时，PAPPA-A KO 雌性的平均产仔数总体减少。与 WT 对照组相比，PAPP-A KO 小鼠的排卵卵母细胞数量减少，给予马绒毛膜促性腺激素后血清雌二醇水平降低，注射人绒毛膜促性腺激素后血清孕酮水平降低，卵巢甾体生成酶基因表达降低。在 PAPP-A KO 小鼠中，促性腺激素刺激后抑制性 IGFBP2、IGFBP3 和 IGFBP4 卵巢基因表达减少，表明卵巢 IGF 系统内存在一些代偿。卵泡刺激素受体、黄体生成素受体和卵丘扩展所需基因的表达水平不受影响。对排卵前卵泡液的分析表明，PAPP-A KO 小鼠 IGFBP4 蛋白水解活性完全丧失，表明在体内缺乏 PAPPA 蛋白水解活性时，其他 IGFBP 蛋白酶不能代偿缺失。综上所述，这些数据表明 PAPPA 通过控制卵巢 IGF 的生物利用度，在调节卵巢功能和雌性生育能力方面发挥重要作用。
