Human stanniocalcin-2 exhibits potent growth-suppressive properties in transgenic mice independently of growth hormone and IGFs
Human stanniocalcin-2 exhibits potent growth-suppressive properties in transgenic mice independently of growth hormone and IGFs
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DOI：
10.1152/ajpendo.00268.2004
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发表时间：
2005-01-01
影响因子：
5.1
通讯作者：
DiMattia, GE
中科院分区：
文献类型：
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作者：
Gagliardi, AD;Kuo, EYW;DiMattia, GE
斯钙素（STC）-2是通过其与激素STC-1的一级氨基酸序列同一性而发现的。STC-2的功能尚未被检测;因此，我们产生了两个过表达人（h）STC-2的转基因小鼠系，以通过鉴定明显的表型来深入了解其潜在功能。小鼠Stc 2基因表达的分析表明，与Stc 1不同，它在发育过程中表达不高，但在成年小鼠中与Stc 1重叠表达，心脏和骨骼肌中Stc 2 mRNA的稳态水平最高。hSTC-2的组成性过表达导致早在胚胎第12.5天的出生前和出生后生长受限，进展使得成熟的hSTC-2转基因小鼠比野生型同窝仔小45%。hSTC-2过表达有时是致命的;我们观察到26 - 34%的新生儿发病率没有明显的畸形。hSTC-2诱导的生长迟缓与发育迟缓相关，最显著的是颅缝形成。器官异速生长研究表明，hSTC-2诱导的侏儒症与睾丸器官肿大和骨骼肌质量的显著减少相关，可能导致侏儒表型。hSTC-2转基因小鼠也是高吞噬的，但这不会导致肥胖。在hSTC-2转基因小鼠中，血清Ca 2+和PO 4没有变化，尽管STC-1可以调节哺乳动物的细胞内和细胞外Ca 2+。有趣的是，hSTC-2诱导的严重生长迟缓与GH或IGF表达的降低无关。因此，与STC-1相似，STC-2可作为有效的生长抑制剂并减少膜内和软骨内骨发育和骨骼肌生长，这意味着这些组织是斯钙素的特异性生理靶点。
Stanniocalcin (STC)-2 was discovered by its primary amino acid sequence identity to the hormone STC-1. The function of STC-2 has not been examined; thus we generated two lines of transgenic mice overexpressing human ( h) STC-2 to gain insight into its potential functions through identification of overt phenotypes. Analysis of mouse Stc2 gene expression indicates that, unlike Stc1, it is not highly expressed during development but exhibits overlapping expression with Stc1 in adult mice, with heart and skeletal muscle exhibiting highest steady-state levels of Stc2 mRNA. Constitutive overexpression of hSTC-2 resulted in pre- and postnatal growth restriction as early as embryonic day 12.5, progressing such that mature hSTC-2-transgenic mice are similar to 45% smaller than wild-type littermates. hSTC-2 overexpression is sometimes lethal; we observed 26 - 34% neonatal morbidity without obvious dysmorphology. hSTC-2-induced growth retardation is associated with developmental delay, most notably cranial suture formation. Organ allometry studies show that hSTC-2-induced dwarfism is associated with testicular organomegaly and a significant reduction in skeletal muscle mass likely contributing to the dwarf phenotype. hSTC-2-transgenic mice are also hyperphagic, but this does not result in obesity. Serum Ca2+ and PO4 were unchanged in hSTC-2-transgenic mice, although STC-1 can regulate intra- and extracellular Ca2+ in mammals. Interestingly, severe growth retardation induced by hSTC-2 is not associated with a decrease in GH or IGF expression. Consequently, similar to STC-1, STC-2 can act as a potent growth inhibitor and reduce intramembranous and endochondral bone development and skeletal muscle growth, implying that these tissues are specific physiological targets of stanniocalcins.