IGF-I GENE EXPRESSION AND SKELETAL INTEGRITY

17.肌肉骨骼老化的基本机制。胰岛素样生长因子-I（IGF-1）是一种重要的骨合成代谢剂。 肝源性血清IGF-I和局部产生的IGF-I在骨骼维护中都很重要，但这些部位的IGF-I生物合成可能受不同的细胞外因子控制。 此外，尚未明确的组织特异性因素是重要的IGF-I基因表达的建立。 事实上，最近的研究表明，一系列的血清IGF-I水平存在于人类，这些可能是某些年龄相关疾病，包括骨质疏松性骨折的发展预测。 因此，血清和局部IGF-I产生的变化可能是老年人骨质疏松症的重要病因。 两个近交系小鼠品系C57 BL 6和C3 H/HeJ分别表现出较低和较高的血清IGF-I水平、骨矿物质密度、骨IGF-I含量、从培养的成骨细胞释放的IGF-I以及由在肝脏和骨中有活性的两个启动子（P2）中的第二个转录产生的肝脏含有IGF-I外显子2的mRNA的水平。 这些变化与GH、胰岛素或小鼠营养状态的任何差异无关，因为它们保存在培养的细胞中，我们假设遗传性、细胞自主性因素的差异导致IGF-I产生和骨密度的差异。 为了检验这一假设，我们建议1）确定IGF-I外显子2转录本是否在骨和成骨细胞培养物中增加，如在肝脏中所示; 2）确定外显子2转录本的变化是否是由于转录的变化; 3）确定两种菌株中外显子2启动子区（P2）是否存在任何序列差异。 这些目标的结果将阐明是否顺式作用元件，反式作用因子，或两者引起IGF-I基因转录或mRNA稳定性的变化，导致IGF-I肽合成的变化，这些影响是否延伸到所有组织表达外显子2转录本，包括培养细胞，因此，是否影响是由于遗传，细胞自主因素。此外，这些数据是必不可少的未来研究，旨在确定IGF-I基因表达的变化的详细机制，包括遗传性细胞自主因素的具体定义。最后，这些结果将是必不可少的未来的研究，旨在确定是否遗传性的变化，肝脏外显子2转录导致收购和维护的骨密度在这些小鼠品系和人类受试者谁表现出不同的血清IGF-I水平和骨质疏松症的可变风险的差异。

17. Basic underlying mechanisms of musculoskeletal aging. Insulin-like growth factor-I (IGF-1) is an important anabolic agent in bone. Both liver-derived serum IGF-I and locally produced IGF-I are important in skeletal maintenance, but IGF-I biosynthesis in these sites may be controlled by different extracellular factors. Moreover, as yet ill-defined tissue-specific factors are important in the establishment of IGF-I gene expression. Indeed, recent studies indicate that a range of serum IGF-I levels exist in humans, and these may be predictive for the development of certain age-related disorders, including osteoporotic fractures. Thus, changes in serum and local IGF-I production could be critical in the etiology of osteoporosis in the elderly. Two inbred mouse strains, C57BL6, and C3H/HeJ exhibit, respectively, lower and higher serum IGF-I levels, bone mineral density, bone IGF-I content, IGF-I release from cultured osteoblasts, and levels of liver IGF-I exon 2-containing mRNAs that result from .transcription from the second of two promoters (P2) active in liver and bone. These changes are not associated with any differences in GH, insulin or nutritional status of the mice and because they are preserved in cultured cells, we hypothesize that differences in heritable, cell-autonomous factors result in differences in IGF-I production and bone mineral density. In order to test this hypothesis we propose 1) to determine whether IGF-I exon 2 transcripts are increased in bone and osteoblast cultures as demonstrated in liver; 2) to define whether the changes in exon 2 transcripts are due to changes in transcription; and 3) to determine whether there are any sequence differences in the exon 2 promoter region (P2) in the two strains. Outcomes of these aims will elucidate whether cis-acting elements, trans-acting factors, or both cause changes in IGF-I gene transcription or mRNA stability that result in changes in IGF-I peptide synthesis, whether these effects extend to all tissues that express exon 2 transcripts, including cells in culture, and therefore, whether the effects are due to heritable, cell-autonomous factors. Moreover, these data are essential to future studies designed to determine the detailed mechanisms of the changes in IGF-I gene expression, including specific definition of the heritable cell autonomous factors. Finally, these outcomes will be essential to future studies designed to determine whether heritable changes in liver exon 2 transcription lead to differences in acquisition and maintenance of bone mineral density in these mouse strains and in human subjects who exhibit differences in serum IGF-I levels and variable risk for osteoporosis.