Gender-specific changes in bone turnover and skeletal architecture in igfbp-2-null mice.
IGF-binding protein-2 (IGFBP-2) is a 36-kDa protein that binds to the IGFs with high affinity. To determine its role in bone turnover, we compared Igfbp2(-/-) mice with Igfbp2(+/+) colony controls. Igfbp2(-/-) males had shorter femurs and were heavier than controls but were not insulin resistant. Serum IGF-I levels in Igfbp2(-/-) mice were 10% higher than Igfbp2(+/+) controls at 8 wk of age; in males, this was accompanied by a 3-fold increase in hepatic Igfbp3 and Igfbp5 mRNA transcripts compared with Igfbp2(+/+) controls. The skeletal phenotype of the Igfbp2(-/-) mice was gender and compartment specific; Igfbp2(-/-) females had increased cortical thickness with a greater periosteal circumference compared with controls, whereas male Igfbp2(-/-) males had reduced cortical bone area and a 20% reduction in the trabecular bone volume fraction due to thinner trabeculae than Igfbp2(+/+) controls. Serum osteocalcin levels were reduced by nearly 40% in Igfbp2(-/-) males, and in vitro, both CFU-ALP(+) preosteoblasts, and tartrate-resistant acid phosphatase-positive osteoclasts were significantly less abundant than in Igfbp2(+/+) male mice. Histomorphometry confirmed fewer osteoblasts and osteoclasts per bone perimeter and reduced bone formation in the Igfbp2(-/-) males. Lysates from both osteoblasts and osteoclasts in the Igfbp2(-/-) males had phosphatase and tensin homolog (PTEN) levels that were significantly higher than Igfbp2(+/+) controls and were suppressed by addition of exogenous IGFBP-2. In summary, there are gender- and compartment-specific changes in Igfbp2(-/-) mice. IGFBP-2 may regulate bone turnover in both an IGF-I-dependent and -independent manner.
DeMambro
V E
VE
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. veg@jax.org
Clemmons
D R
DR
Horton
L G
LG
Bouxsein
M L
ML
Wood
T L
TL
Beamer
W G
WG
Canalis
E
E
Rosen
C J
CJ
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001823:Body Composition / Q000235:genetics; D015519:Bone Density / Q000235:genetics; D016723:Bone Remodeling / Q000235:genetics*; D001842:Bone and Bones / Q000033:anatomy & histology*; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000033:anatomy & histology; D005947:Glucose / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015675:Osteocalcin / Q000097:blood; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D012727:Sex Characteristics
D018971:Insulin-Like Growth Factor Binding Protein 2; D018969:Insulin-Like Growth Factor Binding Proteins; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D051059:PTEN Phosphohydrolase; D005947:Glucose