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

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. Copyright © 2008 by The Endocrine Society.