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Submitted on June 29, 2004
Accepted on November 4, 2004
Laboratory of Molecular Signalling, The Babraham Institute, Cambridge, UK; Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, California, USA; Departments of Medicine and Biochemistry, Loma Linda University, California, USA
* To whom correspondence should be addressed. E-mail: Subburaman.Mohan{at}med.va.gov.
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 BMD we generated transgenic (Tg) mice overexpressing Igfbp5 using a CMV enhancer and 
-actin promoter (CMV/A). Tg animals showed an increase in serum IGFBP-5 concentrations by 7.7- to 3.5-fold at 3 to 8 weeks of age respectively. Concentrations were 6-49% higher for males compared with females, in both WT 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 WT, assessed by dual energy x-ray absorptiometry; DEXA). Significant gender differences in BMD were confirmed by peripheral quantitative computed tomography (pQCT). Histomorphometry revealed that while bone formation rate (BFR) and mineralising surface (MS) 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 nulls.
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 and so provides the first in vivo evidence, by genetic manipulation, for IGF-independent actions of IGFBP-5 in bone function. This study has implications for the gender-biased progression of osteoporosis.
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