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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aorta / metabolism
  • Body Composition / genetics
  • Bone Density / genetics
  • Bone Remodeling / genetics*
  • Bone and Bones / anatomy & histology*
  • Cells, Cultured
  • Female
  • Femur / anatomy & histology
  • Glucose / metabolism
  • Insulin-Like Growth Factor Binding Protein 2 / blood
  • Insulin-Like Growth Factor Binding Protein 2 / genetics*
  • Insulin-Like Growth Factor Binding Protein 2 / metabolism
  • Insulin-Like Growth Factor Binding Proteins / blood
  • Insulin-Like Growth Factor Binding Proteins / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteocalcin / blood
  • PTEN Phosphohydrolase / metabolism
  • Sex Characteristics*

Substances

  • Insulin-Like Growth Factor Binding Protein 2
  • Insulin-Like Growth Factor Binding Proteins
  • Osteocalcin
  • Insulin-Like Growth Factor I
  • PTEN Phosphohydrolase
  • Glucose