PDF(Pubmed)
Abstract：
BACKGROUND: Children with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways.
METHODS: Plasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed.
RESULTS: Reduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3β, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females.
CONCLUSIONS: Sex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.
Understanding the physiological role of pregnancy-associated plasma protein-A2 (PAPP-A2), a proteinase involved in the insulin-like growth factor-1 (IGF1) availability to regulate growth, could provide insight into new treatments for patients with short stature and skeletal abnormalities. Although progressive postnatal growth retardation in patients with PAPP-A2 mutations can differ between males and females, we do not know the underlying differences in IGF1 system and signaling, and their response to treatment that contribute to growth improvement. The present study examines whether Pappa2 deficiency and pharmacological administration of rhGH, rhIGF1 and rhPAPP-A2 are associated with sex-specific differences in IGF1 ternary complexes and IGF1 signaling pathways. Reduced body and femur length of Pappa2-deficient mice was associated with sex- and tissue-specific alteration of IGF ternary/binary complexes and IGF1 signaling pathways. rhPAPP-A2 treatment induced female-specific increase in body and femur length and reduction in IGF ternary/binary complexes through STAT5-AKT-ERK2-AMPK signaling pathways in liver. The involvement of PAPP-A2 in sex-based growth physiology supports the use of promising drugs to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.
METHODS: Plasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed.
RESULTS: Reduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3β, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females.
CONCLUSIONS: Sex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.
Understanding the physiological role of pregnancy-associated plasma protein-A2 (PAPP-A2), a proteinase involved in the insulin-like growth factor-1 (IGF1) availability to regulate growth, could provide insight into new treatments for patients with short stature and skeletal abnormalities. Although progressive postnatal growth retardation in patients with PAPP-A2 mutations can differ between males and females, we do not know the underlying differences in IGF1 system and signaling, and their response to treatment that contribute to growth improvement. The present study examines whether Pappa2 deficiency and pharmacological administration of rhGH, rhIGF1 and rhPAPP-A2 are associated with sex-specific differences in IGF1 ternary complexes and IGF1 signaling pathways. Reduced body and femur length of Pappa2-deficient mice was associated with sex- and tissue-specific alteration of IGF ternary/binary complexes and IGF1 signaling pathways. rhPAPP-A2 treatment induced female-specific increase in body and femur length and reduction in IGF ternary/binary complexes through STAT5-AKT-ERK2-AMPK signaling pathways in liver. The involvement of PAPP-A2 in sex-based growth physiology supports the use of promising drugs to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.
摘要：
背景：患有妊娠相关血浆蛋白A2（PAPP-A2）突变导致生物活性胰岛素样生长因子-1（IGF1）水平低和进行性出生后生长迟缓的儿童在重组人（rh）IGF1治疗后具有改善的生长速度和身高。本研究旨在评估Pappa2缺乏和GH/IGF1系统的药理学操作是否与生长相关信号通路的性别特异性差异有关。
方法：等离子，下丘脑,两种性别的Pappa2ko/ko小鼠的垂体和肝脏，显示骨骼生长减少，这些用rhGH治疗的小鼠的肝脏，分析出生后第5天至PND35天的rhIGF1和rhPAPP-A2。
结果：Pappa2ko/ko小鼠的身体和股骨长度减少与以下方面的增加有关：（1）血浆中IGF1三元复合物（IGF1，IGFBP5/Igfbp5，Igfbp3，Igfals）的成分，下丘脑和/或肝脏；和（2）关键信号调节因子（磷酸化PI3K，AKT,mTOR,GSK3β,下丘脑ERK1/2和AMPKα），垂体和/或肝脏，Pappa2ko/ko雌性具有更突出的效果。与rhGH和rhIGF1相比，rhPAPP-A2特异性诱导：（1）增加的身体和股骨长度，Pappa2ko/ko女性的血浆总IGF1和IGFBP5浓度降低；（2）Igf1和Igf1r水平升高，Ghr降低，Pappa2ko/ko雌性肝脏中的Igfbp3和Igfals水平。这些变化伴随着Pappa2ko/ko雌性肝脏中较低的磷酸-STAT5，磷酸-AKT和磷酸-ERK2水平和较高的磷酸-AMPK水平。
结论：IGF1系统和信号通路的性别特异性差异与Pappa2缺乏有关，指出rhPAPP-A2是一种有前途的药物，可以以女性特异性方式缓解低IGF1生物利用度的出生后生长迟缓。
了解妊娠相关血浆蛋白-A2（PAPP-A2）的生理作用，参与胰岛素样生长因子-1（IGF1）可用性调节生长的蛋白酶，可以为身材矮小和骨骼异常的患者提供新的治疗方法。尽管PAPP-A2突变患者的进行性产后生长迟缓在男性和女性之间可能有所不同，我们不知道IGF1系统和信号的潜在差异，以及他们对有助于增长的治疗的反应。本研究检查了Pappa2缺乏症和rhGH的药物给药，rhIGF1和rhPAPP-A2与IGF1三元复合物和IGF1信号通路的性别特异性差异有关。Pappa2缺陷小鼠的身体和股骨长度减少与IGF三元/二元复合物和IGF1信号通路的性别和组织特异性改变有关。rhPAPP-A2治疗通过肝脏中的STAT5-AKT-ERK2-AMPK信号通路诱导女性特异性增加身体和股骨长度，并减少IGF三元/二元复合物。PAPP-A2参与基于性别的生长生理学支持使用有希望的药物以女性特异性方式缓解低IGF1生物利用度的出生后生长迟缓。
方法：等离子，下丘脑,两种性别的Pappa2ko/ko小鼠的垂体和肝脏，显示骨骼生长减少，这些用rhGH治疗的小鼠的肝脏，分析出生后第5天至PND35天的rhIGF1和rhPAPP-A2。
结果：Pappa2ko/ko小鼠的身体和股骨长度减少与以下方面的增加有关：（1）血浆中IGF1三元复合物（IGF1，IGFBP5/Igfbp5，Igfbp3，Igfals）的成分，下丘脑和/或肝脏；和（2）关键信号调节因子（磷酸化PI3K，AKT,mTOR,GSK3β,下丘脑ERK1/2和AMPKα），垂体和/或肝脏，Pappa2ko/ko雌性具有更突出的效果。与rhGH和rhIGF1相比，rhPAPP-A2特异性诱导：（1）增加的身体和股骨长度，Pappa2ko/ko女性的血浆总IGF1和IGFBP5浓度降低；（2）Igf1和Igf1r水平升高，Ghr降低，Pappa2ko/ko雌性肝脏中的Igfbp3和Igfals水平。这些变化伴随着Pappa2ko/ko雌性肝脏中较低的磷酸-STAT5，磷酸-AKT和磷酸-ERK2水平和较高的磷酸-AMPK水平。
结论：IGF1系统和信号通路的性别特异性差异与Pappa2缺乏有关，指出rhPAPP-A2是一种有前途的药物，可以以女性特异性方式缓解低IGF1生物利用度的出生后生长迟缓。
了解妊娠相关血浆蛋白-A2（PAPP-A2）的生理作用，参与胰岛素样生长因子-1（IGF1）可用性调节生长的蛋白酶，可以为身材矮小和骨骼异常的患者提供新的治疗方法。尽管PAPP-A2突变患者的进行性产后生长迟缓在男性和女性之间可能有所不同，我们不知道IGF1系统和信号的潜在差异，以及他们对有助于增长的治疗的反应。本研究检查了Pappa2缺乏症和rhGH的药物给药，rhIGF1和rhPAPP-A2与IGF1三元复合物和IGF1信号通路的性别特异性差异有关。Pappa2缺陷小鼠的身体和股骨长度减少与IGF三元/二元复合物和IGF1信号通路的性别和组织特异性改变有关。rhPAPP-A2治疗通过肝脏中的STAT5-AKT-ERK2-AMPK信号通路诱导女性特异性增加身体和股骨长度，并减少IGF三元/二元复合物。PAPP-A2参与基于性别的生长生理学支持使用有希望的药物以女性特异性方式缓解低IGF1生物利用度的出生后生长迟缓。
