Growth inhibition in giant growth hormone transgenic mice by overexpression of insulin-like growth factor-binding protein-2
Growth inhibition in giant growth hormone transgenic mice by overexpression of insulin-like growth factor-binding protein-2
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DOI：
10.1210/en.142.5.1889
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发表时间：
2001-05-01
期刊：
影响因子：
4.8
通讯作者：
Wolf, E
中科院分区：
文献类型：
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作者：
Hoeflich, A;Nedbal, S;Wolf, E
为了阐明胰岛素样生长因子（IGF）结合蛋白2（IGFBP-2）在出生后生长调节中的作用，我们将半合子CMV-IGFBP-2转基因小鼠与半合子PEPCK-bGH转基因小鼠杂交，其特征是血清GH水平在2μg/ml范围内。获得了四个遗传组：携带两种转基因（GB）、GH（G）或IGFBP-2转基因（B）的动物，以及非转基因对照（C）。分析雄性后代的 IGF-I 血清水平、IGFBP-2 血清和组织水平以及身体和器官生长。 GH 过表达组的血清 IGF-I 水平增加了 2 至 3 倍（P < 0.001），G 和 GB 小鼠之间没有差异。与 C 和 G 小鼠相比，B 和 GB 小鼠的血清 IGFBP-2 水平增加了 4 至 9 倍（P < 0.001）。 Western免疫印迹分析没有揭示B和GB小鼠之间组织IGFBP-2水平的差异。 IGFBP-2 水平在胰腺中最高，其次是骨骼肌、心脏、肾脏、大脑、皮肤和脾脏。肝脏中未发现 IGFBP-2 升高。与 C 和 B 小鼠相比，G 和 GB 小鼠的体重增加显着增加，导致 15 周龄时体重几乎增加了 2 倍。然而，与 G 小鼠相比，GB 小鼠的体重显着降低（17%；P < 0.001），与 C 小鼠相比，B 小鼠的体重显着降低（13%；P < 0.05）。这主要是由于胴体重量显着减少所致（GB us. G，27%；B us. C，21%；P < 0.001）。对 5 周龄和 15 周龄小鼠的鼻臀长度、器官（脑、心脏、脾脏、肝脏、胰腺、肾脏）和组织重量（皮肤、胴体、腹部脂肪）的测量揭示了一些迹象，表明 IGFBP-2 过表达的生长抑制作用在高 GH/IGF-I 小鼠中更为明显：1) 在 5 周龄时，GB 小鼠表现出所有 与G小鼠相比，除腹部脂肪重量外的生长参数均显着降低，而B小鼠与C小鼠相比，仅脑重量显着降低。 2) 在 15 周龄动物中，GB us 中除脾脏和腹部脂肪重量外，所有生长参数均显着下降。 G 小鼠与 C 小鼠相比，只有鼻臀长度以及胴体和大脑的重量显着减少。我们的研究首次证明了 IGFBP-2 在巨型转基因小鼠中抑制 GH 刺激的生长的潜力，为该 IGFBP 的体内抑制作用提供了进一步的证据。
To clarify the role of insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) in postnatal growth regulation, we crossed hemizygous CMV-IGFBP-2 transgenic mice with hemizygous PEPCK-bGH transgenic mice, which are characterized by serum GH levels in the range of 2 mug/ml. Four genetic groups were obtained: animals carrying both transgenes (GB), the GH (G) or the IGFBP-2 transgene (B), and nontransgenic controls (C). Male offspring were analyzed for serum levels of IGF-I, for serum and tissue levels of IGFBP-2, and for body and organ growth. Serum IGF-I levels were 2- to 3-fold increased (P < 0.001) in the GH-overexpressing groups, with no difference between G and GB mice. Serum IGFBP-2 levels were 4- to 9-fold (P < 0.001) increased both in B and GB vs. C and G mice. Western immunoblot analysis did not reveal differences in tissue IGFBP-2 levels between B and GB mice. IGFBP-2 levels were highest in pancreas, followed by skeletal muscle, heart, kidney, brain, skin, and spleen. No elevation of IGFBP-2 was found in the liver. Body weight gain of G and GB mice was significantly increased vs. C and B mice, resulting in almost 2-fold increased body weights at the age of 15 weeks. However, there was a significant reduction in body weight of GB vs. G mice (17%; P < 0.001) and of B vs. C mice (13%; P < 0.05). This was primarily caused by a marked reduction of carcass weight (GB us. G, 27%; B us. C, 21%; P < 0.001). Measurements of nose-rump-length, organ (brain, heart, spleen, liver, pancreas, kidney), and tissue weights (skin, carcass, abdominal fat) in 5- and 15-week-old mice revealed several indications that the growth-inhibiting effect of IGFBP-2 overexpression was more marked in high-GH/IGF-I mice: 1) At 5 weeks of age, GB mice displayed a significant reduction of all growth parameters except for the weight of abdominal fat, when compared with G mice, whereas only brain weight was significantly reduced in B vs. C mice. 2) In 15-week-old animals, a significant reduction in all growth parameters, except for spleen and abdominal fat weights, was seen in GB us. G mice, whereas only nose-rump-length and the weights of carcass and brain were significantly reduced in B vs. C mice. Our study demonstrates, for the first time, the potential of IGFBP-2 to inhibit GH-stimulated growth in giant transgenic mice, providing further evidence for an inhibitory effect of this IGFBP in vivo.