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. 2008 May;149(5):2051-61.
doi: 10.1210/en.2007-1068. Epub 2008 Feb 14.

Gender-specific changes in bone turnover and skeletal architecture in igfbp-2-null mice

V E DeMambro  1 , D R Clemmons, L G Horton, M L Bouxsein, T L Wood, W G Beamer, E Canalis, C J Rosen
Affiliations

Gender-specific changes in bone turnover and skeletal architecture in igfbp-2-null mice

V E DeMambro et al. Endocrinology. 2008 May.

Abstract

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.

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Figures

Figure 1
Figure 1
Serum IGFBP-2 levels at 16 wk of age; n = 6 for each genotype and sex. *, P ≤ 0.05 for comparison of male with female Igfbp2+/+.
Figure 2
Figure 2
Micro-CT images at 8 wk of age. A, Cortical compartment for Igfbp2−/− and Igfbp2+/+ control male and females; B, distal trabecular compartment for the Igfbp2−/− and Igfbp2+/+ control males.
Figure 3
Figure 3
Bone marrow stromal cultures of Igfbp2−/− and Igfbp2+/+ control males. A, At d 18 in culture, adherent OB progenitor cells were identified by alkaline phosphatase staining (CFU-ALP) and were counterstained with von Kossa for mineral deposits (CFU-OB); B, numbers of osteoclast cells in the bone marrow stromal cultures of Igfbp2−/− and Igfbp2+/+ control mice. At d 7, the cells were fixed and stained for TRAP. TRAP-positive multinucleated (more than three nuclei) osteoclasts were then counted using light microscopy. The Igfbp2−/− males had a significant reduction in the number of osteoclast cells (*, P ≤ 0.05), whereas there was only a trend for reduced numbers in the Igfbp2−/− females (P = 0.08).
Figure 4
Figure 4
Immunoblot of PTEN. A, Aortas from Igfbp2+/+ controls and Igfbp2−/− males were lysed and processed. After SDS-PAGE, the amount of PTEN was determined by immunoblotting. The arrow denotes the position of the PTEN band. The α-actin control for loading is shown in the lower panel. B, PTEN immunoblot of osteoblast lysates from BMS cultures of Igfbp2+/+ controls and Igfbp2−/− male mice in the basal state (control), treated with 50 ng/ml IGF-I (+ IGF-I), treated with 200 ng/ml IGFBP-2 (+ IGFBP-2), and the combination of both. Data were corrected for the total amount of protein loaded as described in Materials and Methods.
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