Paracrine Overexpression of IGFBP‐4 in Osteoblasts of Transgenic Mice Decreases Bone Turnover and Causes Global Growth Retardation

• Published in: Journal of bone and mineral research Vol. 18; no. 5; pp. 836 - 843
• Main Authors: Zhang, Mei, Faugere, Marie‐Claude, Malluche, Hartmut, Rosen, Clifford J, Chernausek, Steven D, Clemens, Thomas L
• Format: Journal Article
• Language: English
• Published: Washington, DC John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR) 01.05.2003; American Society for Bone and Mineral Research
• Subjects: Animals; Base Sequence; Biological and medical sciences; Bone Development; bone histomorphometry; Bone Remodeling - genetics; DNA Primers; Fundamental and applied biological sciences. Psychology; Growth; Humans; Insulin-Like Growth Factor Binding Protein 4 - genetics; Insulin-Like Growth Factor Binding Protein 4 - physiology; insulin‐like growth factor binding proteins; insulin‐like growth factor‐1; Mice; Mice, Transgenic; osteoblasts; Osteocalcin - genetics; Promoter Regions, Genetic; Skeleton and joints; Transgenes; transgenic mice; Vertebrates: osteoarticular system, musculoskeletal system; Osteocalcin; Rodentia; Transgenic animal; Gene overexpression; insulin-like growth factor-1; Insulin like growth factor 1; Osteoarticular system; Promoter; Insulin like growth factor binding protein; insulin-like growth factor binding proteins; In vivo; Vertebrata; Mammalia; bone histomorphometry; Mouse; transgenic mice; Turnover; Osteoblast; Paracrine secretion; Bone; osteoblasts
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.2003.18.5.836

Insulin‐like growth factor binding protein 4 (IGFBP‐4) is abundantly expressed in bone and is generally believed to function as an inhibitor of IGF action. To investigate the function of locally produced IGFBP‐4 in bone in vivo, we targeted expression of IGFBP‐4 to osteoblasts using a human osteocalcin promoter to direct transgene expression. IGFBP‐4 protein levels in calvaria of transgenic (OC‐BP4) mice as measured by Western ligand blot were increased 25‐fold over the endogenous level. Interestingly, levels of IGFBP‐5 were decreased in the OC‐BP4 mice, possibly because of a compensatory alteration in IGF‐1 action. Morphometric measurements showed a decrease in femoral length and total bone volume in transgenic animals compared with the controls. Quantitative histomorphometry at the distal femur disclosed a striking reduction in bone turnover in the OC‐BP4 mice. Osteoblast number/bone length and bone formation rate/bone surface in OC‐BP4 mice were approximately one‐half that seen in control mice. At birth, OC‐BP4 mice were of normal size and weight but exhibited striking postnatal growth retardation. Organ allometry (mg/g body weight) analysis revealed that, whereas most organs exhibited a proportional reduction in weight, calvarial and femoral wet weights were disproportionally small (∼70% and 80% of control, respectively). In conclusion, paracrine overexpression of IGFBP‐4 in the bone microenvironment markedly reduced cancellous bone formation and turnover and severely impaired overall postnatal skeletal and somatic growth. We attribute these effects to the sequestration of IGF‐1 by IGFBP‐4 and consequent impairment of IGF‐1 action in skeletal tissue.