Ablation of Hepatic Production of the Acid-Labile Subunit in Bovine-GH Transgenic Mice: Effects on Organ and Skeletal Growth
Ablation of Hepatic Production of the Acid-Labile Subunit in Bovine-GH Transgenic Mice: Effects on Organ and Skeletal Growth
复制标题
DOI：
10.1210/en.2016-1952
复制
发表时间：
2017-08-01
期刊：
影响因子：
4.8
通讯作者：
Yakar, Shoshana
中科院分区：
文献类型：
--
作者：
Liu, Zhongbo;Han, Tianzhen;Yakar, Shoshana
生长激素(GH)和胰岛素样生长因子-1(IGF-1)是促进躯体和骨骼生长的合成代谢激素，通过内分泌和自分泌/旁分泌机制调节代谢。我们假设，在血清IGF-1水平降低的状态下，过量的GH组织产生将保护骨骼的生长和完整性。为了验证我们的假设，我们使用牛生长激素(BGH)转基因小鼠作为生长激素高分泌的模型，并去除肝脏衍生的酸不稳定亚基，它稳定了循环中IGF-1与IGF结合蛋白-3和-5的复合体。我们使用遗传学方法创建了BGH/ALS基因敲除(ALSKO)小鼠，并使用小干扰RNA(SiRNA)基因沉默方法来降低ALS或IGF-1的基因表达。我们发现，在这两种模型中，血清中IGF-1水平的降低与BGH小鼠的身体和骨骼尺寸的减小有关。过量的生长激素会产生更坚固的骨骼，但会损害雄性小鼠的机械性能。组织中过量的生长激素分泌不能防止因血清IGF-1降低而导致的骨小梁丢失(在使用siRNAs治疗的BGH/alsko或BGH小鼠中)。BGH小鼠血清IGF-1水平降低并不能缓解高胰岛素血症，也不能解决由GH高分泌引起的肝或肾病变。我们得出结论，即使在生长激素过多的状态下，血清IGF-1水平的降低也会降低躯体和骨骼的生长。
Growth hormone (GH) and insulinlike growth factor 1 (IGF-1) are anabolic hormones that facilitate somatic and skeletal growth and regulate metabolism via endocrine and autocrine/paracrine mechanisms. We hypothesized that excess tissue production of GH would protect skeletal growth and integrity in states of reduction in serum IGF-1 levels. To test our hypothesis, we used bovine GH (bGH) transgenic mice as a model of GH hypersecretion and ablated the liver-derived acid-labile subunit, which stabilizes IGF-1 complexes with IGF-binding protein-3 and -5 in circulation. We used a genetic approach to create bGH/als gene knockout (ALSKO) mice and small interfering RNA (siRNA) gene-silencing approach to reduce als or igf-1 gene expression. We found that in both models, decreased IGF-1 levels in serum were associated with decreased body and skeletal size of the bGH mice. Excess GH produced more robust bones but compromised mechanical properties in male mice. Excess GH production in tissues did not protect from trabecular bone loss in response to reductions in serum IGF-1 (in bGH/ALSKO or bGH mice treated with siRNAs). Reduced serum IGF-1 levels in the bGH mice did not alleviate the hyperinsulinemia and did not resolve liver or kidney pathologies that resulted from GH hypersecretion. We concluded that reduced serum IGF-1 levels decrease somatic and skeletal growth even in states of excess GH.