Postnatal growth and bone mass in mice with IGF-I haploinsufficiency.
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.
He
Jianing
J
Department of Medicine, The University of Connecticut Health Center, Farmington, 06030-1850, USA.
Rosen
Clifford J
CJ
Adams
Douglas J
DJ
Kream
Barbara E
BE
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D015519:Bone Density / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000254:growth & development* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics
D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I