Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
J Bone Miner Res. 2010 Jun;25(6):1257-66. doi: 10.1002/jbmr.20.
Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with recombinant IGF-1 in both children and animals are few. Here, we used two novel transgenic mouse strains to test the long-term effects of elevated circulating IGF-1 on body size and skeletal development. Overexpression of the rat igf1 transgene in livers of mice with otherwise normal IGF-1 expression (HIT mice) resulted in approximately threefold increases in serum IGF-1 levels throughout growth, as well as greater body mass and enhanced skeletal size, architecture, and mechanical properties. When the igf1 transgene was overexpressed in livers of igf1 null mice (KO-HIT), the comparably elevated serum IGF-1 failed to overcome growth and skeletal deficiencies during neonatal and early postnatal growth. However, between 4 and 16 weeks of age, increased serum IGF-1 fully compensated for the absence of locally produced IGF-1 because body weights and lengths of KO-HIT mice became comparable with controls. Furthermore, micro-computed tomography (microCT) analysis revealed that early deficits in skeletal structure of KO-HIT mice were restored to control levels by adulthood. Our data indicate that in the absence of tissue igf1 gene expression, maintaining long-term elevations in serum IGF-1 is sufficient to establish normal body size, body composition, and both skeletal architecture and mechanical function.
使用重组胰岛素样生长因子 1(IGF-1)治疗儿童原发性 IGF-1 缺乏症已变得越来越普遍。未经治疗,原发性 IGF-1 缺乏症可能导致一系列代谢紊乱,包括脂质异常、胰岛素抵抗和骨密度降低。迄今为止,这种治疗的结果被认为是令人鼓舞的;然而,我们对 IGF-1 在发育过程中所起作用的理解仍然有限。关于重组 IGF-1 在儿童和动物中的长期治疗的研究很少。在这里,我们使用两种新型转基因小鼠品系来测试循环 IGF-1 升高对体型和骨骼发育的长期影响。在 otherwise normal IGF-1 表达的小鼠(HIT 小鼠)肝脏中过表达大鼠 igf1 转基因,导致整个生长过程中血清 IGF-1 水平增加约三倍,体重增加,骨骼增大,结构和机械性能增强。当 igf1 转基因在 igf1 缺失型小鼠(KO-HIT)的肝脏中过表达时,可比的升高的血清 IGF-1 未能克服新生儿和早期产后生长中的生长和骨骼缺陷。然而,在 4 至 16 周龄之间,升高的血清 IGF-1 完全补偿了局部产生的 IGF-1 的缺乏,因为 KO-HIT 小鼠的体重和长度变得与对照组相当。此外,微计算机断层扫描(microCT)分析表明,KO-HIT 小鼠骨骼结构的早期缺陷在成年时恢复到对照水平。我们的数据表明,在没有组织 igf1 基因表达的情况下,维持血清 IGF-1 的长期升高足以建立正常的体型、身体成分以及骨骼结构和机械功能。