Postnatal growth and bone mass in mice with IGF-I haploinsufficiency.

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Animals-Newborn, Body-Weight, Bone-Density, Cell-Differentiation, Cell-Proliferation, Cells-Cultured, Female, Femur, Insulin-Like-Growth-Factor-I, Male, Mice, Osteoclasts, RNA-Messenger

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Bone 2006 Jun; 38(6):826-35.


We examined the influence of IGF-I haploinsufficiency on growth, bone mass and osteoblast differentiation in Igf1 heterozygous knockout (HET) mice. Cohorts of male and female wild type (WT) and HET mice in the outbred CD-1 background were analyzed at 1, 2, 4, 8, 12, 15 and 18 months of age for body weight, serum IGF-I and bone morphometry. Compared to WT mice, HET mice had 20-30% lower serum IGF-I levels in both genders and in all age groups. Female HET mice showed significant reductions in body weight (10-20%), femur length (4-6%) and femoral bone mineral density (BMD) (7-12%) before 15 months of age. Male HET mice showed significant differences in all parameters at 2 months and thereafter. At 8 and 12 months, WT mice also showed a significant gender effect: despite their lower body weight, female mice had higher femoral BMD and femur length compared to males. Microcomputed tomography showed a significant reduction in cortical bone area (7-20%) and periosteal circumference (5-13%) with no consistent pattern of change in trabecular bone measurements in 2- and 8-month old HET mice in both genders. HET primary osteoblast cultures showed a 40% reduction in IGF-I protein expression and a 50% decrease in IGF-I mRNA expression. Cell growth and proliferation were decreased in HET cultures. Thus, IGF-I haploinsufficiency in outbred male and female mice resulted in reduced body weight, femur length and areal BMD at most ages. Serum IGF-I levels showed a high level of positive correlation with body weight and skeletal morphometry. These studies show that IGF-I is a determinant of bone size and mass in postnatal life. We speculate that impaired osteoblast proliferation may contribute to the skeletal phenotype of mice with IGF-I haploinsufficiency.