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Perturbations in Bone Formation and Resorption in Insulin‐Like Growth Factor Binding Protein‐3 Transgenic Mice
Author(s) -
Silha Josef V,
Mishra Suresh,
Rosen Clifford J,
Beamer Wesley G,
Turner Russell T,
Powell David R,
Murphy Liam J
Publication year - 2003
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2003.18.10.1834
Subject(s) - endocrinology , medicine , osteoblast , bone resorption , osteoclast , deoxypyridinoline , osteocalcin , resorption , growth factor , genetically modified mouse , chemistry , bone remodeling , insulin like growth factor , transgene , biology , receptor , alkaline phosphatase , biochemistry , gene , in vitro , enzyme
IGF‐I and their binding proteins are important in bone health. Examination of BMD, osteoblast proliferation, and markers of bone resorption in transgenic mice that constitutively overexpress IGFBP‐3 indicates that overexpression of IGFBP‐3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation. Introduction: Low serum insulin‐like growth factor I (IGF‐I) levels correlate with an increased risk of osteoporotic fractures. Serum IGF‐I is largely bound to IGF‐binding protein‐3 (IGFBP‐3), which can inhibit IGF‐I action and enhance delivery of IGF‐I to tissues. Its role in bone biology is unclear. Methods: Bone mineral density (BMD), osteoblast proliferation, and markers of bone resorption were examined in transgenic (Tg) mice that constitutively overexpressed human IGFBP‐3 cDNA driven by either the cytomegalovirus (CMV) or phosphoglycerate kinase (PGK) promoter. Results: Cultured calvarial osteoblasts from Tg mice expressed the transgene and grew more slowly than cells from wild‐type (Wt) mice, and the mitogenic response to IGF‐I was attenuated in osteoblasts from Tg mice. Total volumetric BMD and cortical BMD, measured in the femur using peripheral quantitative computed tomography (pQCT) were significantly reduced in both Tg mouse strains compared with Wt mice. PGKBP‐3 Tg mice showed the most marked reduction in bone density. Osteocalcin levels were similar in Wt and CMVBP‐3 Tg mice but were significantly reduced in PGKBP‐3 Tg mice. Urinary deoxypyridinoline and osteoclast perimeter, markers of bone resorption, were significantly increased in both Tg mouse strains compared with Wt mice. Using double labeling with tetracycline, we demonstrated that pericortical and endocortical mineral apposition rate was significantly reduced in PGKBP‐3 Tg mice compared with Wt mice. Conclusions: These data show that overexpression of IGFBP‐3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation.