Conditional deletion of insulin-like growth factor-I in collagen type 1α2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion
Conditional deletion of insulin-like growth factor-I in collagen type 1α2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion
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DOI：
10.1210/en.2007-0608
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发表时间：
2007-12-01
期刊：
影响因子：
4.8
通讯作者：
Mohan, Subburaman
中科院分区：
文献类型：
--
作者：
Govoni, Kristen E.;Wergedal, Jon E.;Mohan, Subburaman
IGF-I通过内分泌和局部、自分泌/旁分泌途径发挥作用。内分泌和局部IGF-I作用的中断会导致新生儿死亡和包括骨骼在内的各种组织的生长受损；然而，内分泌IGF-I作用中断引起的生长和骨骼表型的严重程度远远低于IGF-I完全中断的情况。基于这些数据和骨细胞高丰度表达IGF-I的事实，我们和其他人预测，局部产生的IGF-I在调节生长和骨生长方面也是关键的。为了确定局部IGF-I的作用，将IGF-I loxP小鼠与IGF-Iα2胶原-Cre小鼠杂交，产生Cre+(条件突变)和Cre-(对照)loxP纯合子小鼠。令人惊讶的是，大约40%-50%的条件突变在出生时死亡，这类似于IGF-I的完全中断，但在缺乏循环IGF-I的小鼠中没有观察到。在条件突变体中，IGF-I在骨骼和肌肉中的表达显著降低，而在肝脏和脑中的表达不明显。因此，循环中的血清IGF-I水平也不受影响。局部IGF-I的破坏显著降低了生长期小鼠的体重28-37%，股骨面积骨密度10-25%，股骨骨大小18-24%。此外，矿化作用早在胚胎发育期间就减少了。组织形态计量学分析一致地确定成骨细胞功能受损，表现为矿物质沉积率(14-30%)和骨形成率(35-57%)降低。总之，局部和内分泌的IGF-I作用都参与调节包括骨骼在内的各种组织的生长，但它们通过不同的机制发挥作用。
IGF-I acts through endocrine and local, autocrine/paracrine routes. Disruption of both endocrine and local IGF-I action leads to neonatal lethality and impaired growth in various tissues including bone; however, the severity of growth and skeletal phenotype caused by disruption of endocrine IGF-I action is far less than with total IGF-I disruption. Based on these data and the fact that bone cells express IGF-I in high abundance, we and others predicted that locally produced IGF-I is also critical in regulating growth and bone accretion. To determine the role of local IGF-I, type 1 alpha 2 collagen-Cre mice were crossed with IGF-I loxP mice to generate Cre+ (conditional mutant) and Cre-(control) loxP homozygous mice. Surprisingly, approximately 40-50% of the conditional mutants died at birth, which is similar to total IGF-I disruption, but not observed in mice lacking circulating IGF-I. Expression of IGF-I in bone and muscle but not liver and brain was significantly decreased in the conditional mutant. Accordingly, circulating levels of serum IGF-I were also not affected. Disruption of local IGF-I dramatically reduced body weight 28-37%, femur areal bone mineral density 10-25%, and femur bone size 18-24% in growing mice. In addition, mineralization was reduced as early as during embryonic development. Consistently, histomorphometric analysis determined impaired osteoblast function as demonstrated by reduced mineral apposition rate (14-30%) and bone formation rate (35-57%). In conclusion, both local and endocrine IGF-I actions are involved in regulating growth of various tissues including bone, but they act via different mechanisms.