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National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland, USA
1 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
2 St Francis Hospital and Medical Center, Hartford, Connecticut, USA
3 Yale University School of Medicine, New Haven, Connecticut, USA
4 Mattel Hospital for Children, Los Angeles California, USA
5 The Department of Animal Science, Cornell University, Ithaca, New York, USA
6 The Jackson Laboratory, Bar Harbor, Maine, USA
7 Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
(Requests for offprints should be addressed to C J Rosen at Maine Center for Osteoporosis Research and Education, St Joseph Hospital, 900 Broadway, Bangor, Maine 04401, USA; Email: rofe{at}aol.com)
* (S Yakar and M L Bouxsein contributed equally to the study) The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1–34) for 4 weeks. VEH-treated IGF-I-deficient mice (i.e. LID, ALSKO and LA mice) exhibited reduced cortical cross-sectional area (P = 0.001) compared with CTL mice; in contrast, femoral trabecular bone volume fractions (BV/TV) of the IGF-I-deficient mice were consistently greater than CTL (P<0.01). ALSKO mice exhibited markedly reduced osteoblast number and surface (P<0.05), as well as mineral apposition rate compared with other IGF-I-deficient and CTL mice. Adherent bone marrow stromal cells, cultured in ß-glycerol phosphate and ascorbic acid, showed no strain differences in secreted IGF-I. In response to PTH, there were both compartment- and strain-specific effects. Cortical bone area was increased by PTH in CTL and ALSKO mice, but not in LID or LA mice. In the trabecular compartment, PTH increased femoral and vertebral BV/TV in LID, but not in ALSKO or LA mice. In conclusion, we demonstrated that the presentation of IGF-I as a circulating complex is essential for skeletal remodeling and the anabolic response to PTH. We postulate that the ternary complex itself, rather than IGF-I alone, influences bone acquisition in a compartment-specific manner (i.e. cortical vs trabecular bone).
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