This Article Full Text Full Text (PDF) All Versions of this Article: 146/2/931    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Salih, D. A. M. Articles by Pell, J. M. Search for Related Content PubMed PubMed Citation Articles by Salih, D. A. M. Articles by Pell, J. M.

Insulin-Like Growth Factor-Binding Protein-5 Induces a Gender-Related Decrease in Bone Mineral Density in Transgenic Mice

Laboratory of Molecular Signaling, The Babraham Institute (D.A.M.S., G.T., F.A.L., N.F.A., E.J.C., J.M.P.), Cambridge, United Kingdom CB2 4AT; and Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center (S.M., Y.K., J.E.W., D.J.B.), and Departments of Medicine and Biochemistry, Loma Linda University (S.M., D.J.B.), Loma Linda, California 92357

Address all correspondence and requests for reprints to: Dr. Jennifer M. Pell, Laboratory of Molecular Signaling, The Babraham Institute, Cambridge, United Kingdom CB2 4AT. E-mail: jenny.pell{at}bbsrc.ac.uk. Or to: Dr. Subburaman Mohan, Musculoskeletal Disease Center (151), Jerry L. Pettis Veterans Affairs Medical Center, 11201 Benton Street, Loma Linda, California 92357. E-mail: subburaman.mohan{at}med.va.gov.

IGF-binding protein-5 (IGFBP-5) is abundant in serum and bone during normal skeletal development, but levels decrease in osteoporosis. Studies have shown that IGFBP-5 stimulates markers of bone formation by potentiating IGF actions and by IGF-independent actions. To test the hypothesis that IGFBP-5 promotes the acquisition of bone mineral density (BMD), we generated transgenic (Tg) mice overexpressing Igfbp5 using a cytomegalovirus enhancer and ß-actin promoter (CMV/ßA). Tg animals showed an increase in serum IGFBP-5 concentrations by 7.7- to 3.5-fold at 3–8 wk of age, respectively. Concentrations were 6–49% higher for males compared with females in both wild-type and Tg mice. Surprisingly, BMD decreased in a gender-dependent manner, with Tg male adults affected more severely than Tg females (31.3% vs. 19.2% reduction, respectively, compared with wild-type mice, assessed by dual energy x-ray absorptiometry). Significant gender differences in BMD were confirmed by peripheral quantitative computed tomography. Histomorphometry revealed that although the bone formation rate and mineralizing surface at the periosteum decreased in Tg mice, they increased at the endosteum, suggesting opposing effects of IGFBP-5 on periosteal and endosteal osteoblasts (by altering proliferation or survival). These findings differ from previous observations in Igf1- and Igf2-null animals. In conclusion, IGFBP-5 has a significant influence on BMD acquisition and maintenance that is dependent on gender and age. The phenotype of Igfbp5 mice cannot be explained solely by IGF inhibition; thus, this study provides the first in vivo evidence, by genetic manipulation, for IGF-independent actions of IGFBP-5 in bone function. These findings have implications for the gender-biased progression of osteoporosis.

This article has been cited by other articles:

				A. Mukherjee and P. Rotwein Insulin-Like Growth Factor-Binding Protein-5 Inhibits Osteoblast Differentiation and Skeletal Growth by Blocking Insulin-Like Growth Factor Actions Mol. Endocrinol., May 1, 2008; 22(5): 1238 - 1250. [Abstract] [Full Text] [PDF]

				C. A. Conover Insulin-like growth factor-binding proteins and bone metabolism Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E10 - E14. [Abstract] [Full Text] [PDF]

				K. E. Govoni, J. E. Wergedal, L. Florin, P. Angel, D. J. Baylink, and S. Mohan Conditional Deletion of Insulin-Like Growth Factor-I in Collagen Type 1{alpha}2-Expressing Cells Results in Postnatal Lethality and a Dramatic Reduction in Bone Accretion Endocrinology, December 1, 2007; 148(12): 5706 - 5715. [Abstract] [Full Text] [PDF]

				K. E. Govoni, S. K. Lee, Y.-S. Chung, R. R. Behringer, J. E. Wergedal, D. J. Baylink, and S. Mohan Disruption of insulin-like growth factor-I expression in type II{alpha}I collagen-expressing cells reduces bone length and width in mice Physiol Genomics, August 20, 2007; 30(3): 354 - 362. [Abstract] [Full Text] [PDF]

				X. Qin, J. E. Wergedal, M. Rehage, K. Tran, J. Newton, P. Lam, D. J. Baylink, and S. Mohan Pregnancy-Associated Plasma Protein-A Increases Osteoblast Proliferation in Vitro and Bone Formation in Vivo Endocrinology, December 1, 2006; 147(12): 5653 - 5661. [Abstract] [Full Text] [PDF]

				H. Yasuoka, Z. Zhou, J. M. Pilewski, T. D. Oury, A. M.K. Choi, and C. A. Feghali-Bostwick Insulin-Like Growth Factor-Binding Protein-5 Induces Pulmonary Fibrosis and Triggers Mononuclear Cellular Infiltration Am. J. Pathol., November 1, 2006; 169(5): 1633 - 1642. [Abstract] [Full Text] [PDF]

				J. K. Christians, A. Hoeflich, and P. D. Keightley PAPPA2, an Enzyme That Cleaves an Insulin-Like Growth-Factor-Binding Protein, Is a Candidate Gene for a Quantitative Trait Locus Affecting Body Size in Mice Genetics, July 1, 2006; 173(3): 1547 - 1553. [Abstract] [Full Text] [PDF]

				Y. G. Amaar, B. Tapia, S.-T. Chen, D. J. Baylink, and S. Mohan Identification and characterization of novel IGFBP5 interacting protein: evidence IGFBP5-IP is a potential regulator of osteoblast cell proliferation Am J Physiol Cell Physiol, March 1, 2006; 290(3): C900 - C906. [Abstract] [Full Text] [PDF]

				K. Chase, D. R. Carrier, F. R. Adler, E. A. Ostrander, and K. G. Lark Interaction between the X chromosome and an autosome regulates size sexual dimorphism in Portuguese Water Dogs Genome Res., December 1, 2005; 15(12): 1820 - 1824. [Abstract] [Full Text] [PDF]