GENETIC REGULATION OF IGF-I IN PEAK BONE DENSITY OF MICE

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DESCRIPTION (provided by applicant): Insulin-like growth factor I (IGF-I) is a critical determinant of peak bone acquisition as demonstrated by association studies of IGF-I gene polymorphisms and bone mineral density (BMD), and experimental genomic manipulations that dramatically impact bone growth and maintenance. Our recent work has focused on the working hypothesis that the serum IGF-I phenotype is a complex heritable trait determined by multiple genetic factors critical for bone acquisition, and identifiable through a QTL (quantitative trait locus) strategy. We previously mapped 4 QTL accounting for nearly half the difference in circulating IGF-I between two inbred strains: C3H/HeJ (C3H) and C57BL/6J (B6). We then identified a major Igf-I QTL on chromosome (Chr) 6 which was associated with low serum IGF-I particularly when there was interaction with a locus on the mid region of Chr 11. After generating N10F2 congenic mice for this QTL by introgressing C3H alleles onto a B6 background (Igf1s1:6T), we found significant differences in serum IGF-I compared to B6 as well as markedly reduced cortical and trabecular BMD, and altered fat distribution. 6T mice also demonstrated suppression in hepatic, fat, muscle and skeletal IGF-I mRNA transcripts, which were reflected in functional studies of bone marrow stromal cells that revealed a major alteration in osteoblast lineage allocation. Subsequent experiments allowed us to bypass a genetic roadblock (i.e. an inversion on chr 6 in C3H) and fine map the Igf1s1 QTL to two genes in the lipoxygenase peroxisome proliferators-activator receptor gamma (Ppargamma) pathway. We now propose two specific aims to test the hypothesis that there is a strong interactive effect for the QTL on Chr 6 and 11 that influences both IGF-I and BMD: 1-Identify the Igf1s1 gene on chr 6 and fine map the Chr 11 locus that reduce IGF-I expression and production; 2- Define how the Igf1s1 gene and the Chr 11 interactive locus impact peak bone acquisition. In this proposal we will combine expertise in functional genomics with collaborators in molecular and stromal cell biology to identify a major regulatory gene for IGF-I, its interactive partner, and the role of these genes in osteoblast and adipocyte lineage allocation.