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Paracrine Overexpression of IGFBP‐4 in Osteoblasts of Transgenic Mice Decreases Bone Turnover and Causes Global Growth Retardation
Author(s) -
Zhang Mei,
Faugere MarieClaude,
Malluche Hartmut,
Rosen Clifford J,
Chernausek Steven D,
Clemens Thomas L
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.2003.18.5.836
Subject(s) - endocrinology , medicine , osteoblast , paracrine signalling , bone remodeling , calvaria , cancellous bone , genetically modified mouse , growth factor , osteocalcin , transgene , chemistry , biology , alkaline phosphatase , receptor , anatomy , in vitro , biochemistry , gene , enzyme
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.