Perturbations in bone formation and resorption in insulin-like growth factor binding protein-3 transgenic mice.
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.


BACKGROUND
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.
Department of Physiology, University of Manitoba, Winnipeg, Canada.
Josef V
JV
Silha
Suresh
S
Mishra
Clifford J
CJ
Rosen
Wesley G
WG
Beamer
Russell T
RT
Turner
David R
DR
Powell
Liam J
LJ
Murphy
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D015519:Bone Density; D001842:Bone and Bones / Q000473:pathology*; D002455:Cell Division; D004396:Coloring Agents / Q000494:pharmacology; D003587:Cytomegalovirus / Q000235:genetics; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D010641:Phenotype; D010735:Phosphoglycerate Kinase / Q000235:genetics; D011401:Promoter Regions, Genetic; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
D000596:Amino Acids; D004396:Coloring Agents; D018076:DNA, Complementary; D018972:Insulin-Like Growth Factor Binding Protein 3; D013778:Tetrazolium Salts; D013844:Thiazoles; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; C036020:deoxypyridinoline; D010735:Phosphoglycerate Kinase; C022616:thiazolyl blue