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Gender-Specific Changes in Bone Turnover and Skeletal Architecture in Igfbp-2-Null Mice

The Jackson Laboratory (V.E.D., L.G.H., W.G.B., C.J.R.), Bar Harbor, Maine 04609; University of North Carolina (D.R.C.), Chapel Hill, North Carolina 27514; Beth Israel Deaconess Medical Center (M.L.B.), Boston, Massachusetts 02215; University of New Jersey School of Medicine (T.L.W.), Newark, New Jersey 07103; and St. Francis Hospital (E.C.), Hartford, Connecticut 06105

Address all correspondence and requests for reprints to: Clifford J. Rosen, M.D., The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609. E-mail: rofe{at}aol.com.

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.