Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-04-08 DOI:10.1186/s13293-024-00603-5
María del Mar Fernández-Arjona, Juan Antonio Navarro, Antonio Jesús López-Gambero, Marialuisa de Ceglia, Miguel Rodríguez, Leticia Rubio, Fernando Rodríguez de Fonseca, Vicente Barrios, Julie A. Chowen, Jesús Argente, Patricia Rivera, Juan Suárez
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Abstract

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. 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. 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. 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.
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PAPP-A2缺乏时与生长相关的IGF1信号传导的性别差异:rhGH、rhIGF1和rhPAPP-A2治疗的比较效应
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)水平低下和出生后进行性生长迟缓的儿童在接受重组人(rh)IGF1治疗后,生长速度和身高均有所改善。本研究旨在评估 Pappa2 缺乏症和 GH/IGF1 系统的药物治疗是否与生长相关信号通路的性别特异性差异有关。研究分析了Pappa2ko/ko雌雄小鼠的血浆、下丘脑、垂体和肝脏,这些小鼠从出生后第5天到出生后第35天的骨骼生长减弱,这些小鼠的肝脏接受了rhGH、rhIGF1和rhPAPP-A2治疗。Pappa2ko/ko小鼠身体和股骨长度的减少与以下因素的增加有关:(1) 血浆、下丘脑和/或肝脏中的IGF1三元复合物成分(IGF1、IGFBP5/Igfbp5、Igfbp3、Igfals);以及 (2) 下丘脑、垂体和/或肝脏中的关键信号调节因子(磷酸化PI3K、AKT、mTOR、GSK3β、ERK1/2和AMPKα),其中Pappa2ko/ko雌鼠的影响更为显著。与rhGH和rhIGF1相比,rhPAPP-A2能特异性地诱导:(1)增加Pappa2ko/ko雌性的体长和股长,降低血浆中总IGF1和IGFBP5的浓度;(2)增加Pappa2ko/ko雌性肝脏中Igf1和Igf1r的水平,降低Ghr、Igfbp3和Igfals的水平。伴随这些变化的是,Pappa2ko/ko雌性肝脏中磷酸-STAT5、磷酸-AKT和磷酸-ERK2水平降低,磷酸-AMPK水平升高。IGF1系统和信号通路的性别特异性差异与Pappa2缺乏有关,这表明rhPAPP-A2是一种很有前途的药物,能以女性特异性的方式缓解IGF1生物利用率低引起的产后生长迟缓。妊娠相关血浆蛋白-A2(PAPP-A2)是一种参与胰岛素样生长因子-1(IGF1)可用性调节生长的蛋白酶,了解妊娠相关血浆蛋白-A2(PAPP-A2)的生理作用可为身材矮小和骨骼异常患者提供新的治疗方法。虽然PAPP-A2突变患者出生后的进行性生长迟缓在男性和女性之间会有差异,但我们并不清楚IGF1系统和信号传导的潜在差异,以及他们对治疗的反应,这些差异有助于生长改善。本研究探讨了Pappa2缺乏症以及rhGH、rhIGF1和rhPAPP-A2的药物治疗是否与IGF1三元复合物和IGF1信号通路的性别差异有关。Pappa2缺陷小鼠体长和股骨长度的减少与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处理通过肝脏中的STAT5-AKT-ERK2-AMPK信号通路诱导雌性小鼠体长和股骨长度的增加以及IGF三元/二元复合物的减少。PAPP-A2参与了基于性别的生长生理学,这支持使用有前景的药物,以女性特异性的方式缓解IGF1生物利用率低导致的产后生长迟缓。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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