The authors state that they have no conflicts of interest.
Osteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice†
Article first published online: 4 DEC 2006
Copyright © 2007 ASBMR
Journal of Bone and Mineral Research
Volume 22, Issue 3, pages 347–356, March 2007
How to Cite
Notini, A. J., McManus, J. F., Moore, A., Bouxsein, M., Jimenez, M., Chiu, W. M., Glatt, V., Kream, B. E., Handelsman, D. J., Morris, H. A., Zajac, J. D. and Davey, R. A. (2007), Osteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice. J Bone Miner Res, 22: 347–356. doi: 10.1359/jbmr.061117
- Issue published online: 4 DEC 2009
- Article first published online: 4 DEC 2006
- Manuscript Accepted: 30 NOV 2006
- Manuscript Revised: 3 OCT 2006
- Manuscript Received: 1 JUN 2006
- androgen receptor;
- type 1a1 collagen promoter
The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone.
Introduction: Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts.
Materials and Methods: Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative μCT at 6, 12, and 32 weeks of age (n = 8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test.
Results: μCT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p < 0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p < 0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p < 0.01) and an increase in trabecular separation (p < 0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age.
Conclusions: These findings show that inactivation of the DNA binding–dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding–dependent actions of the AR in mature osteoblasts.