Allelic differences in a quantitative trait locus affecting insulin-like growth factor-I impact skeletal acquisition and body composition

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Abstract
Insulin-like growth factor-I (IGF-I) is critical for optimal skeletal growth and maintenance. Knockout and transgenic models have provided significant insights into the role of IGF-I in bone modeling and remodeling. Congenic mice demonstrate allelic differences in particular quantitative trait loci (QTL). One such model is congenic 6T, which contains a QTL for reduced serum IGF-I donated from C3H/HeJ on a pure C57Bl/6 J (B6) background. In this study we found a 30%–50% reduction in IGF-I expression in bone, liver, and fat of the congenic 6T mouse, as well as lower circulating IGF-I compared with control B6. 6T mice also had a greater percentage body fat, but reduced serum leptin. These changes were associated with reduced cortical and trabecular bone mineral density, impaired bone formation but no change in bone resorption. Moreover, the anabolic skeletal response to intermittent parathyroid hormone (PTH) therapy was blunted in 6T compared with B6, potentially in response to greater programmed cell death in osteocytes and osteoblasts of 6T. In summary, allelic differences in IGF-I expression impact peak bone acquisition and body composition, as well as the skeletal response to PTH. Lifelong changes in circulating and skeletal IGF-I may be relevant for the pathophysiology of several diseases, including chronic renal failure.