IGF-I GENE EXPRESSION AND SKELETAL INTEGRITY

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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.