Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice.
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.


BACKGROUND
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.


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 microCT 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
microCT 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.
Notini
Amanda J
AJ
Department of Medicine, The University of Melbourne, Heidelberg, Victoria, and ANZAC Research Institute, Concord Hospital, Sydney, New South Wales, Australia.
McManus
Julie F
JF
Moore
Alison
A
Bouxsein
Mary
M
Jimenez
Mark
M
Chiu
W S Maria
WS
Glatt
Vaida
V
Kream
Barbara E
BE
Handelsman
David J
DJ
Morris
Howard A
HA
Zajac
Jeffrey D
JD
Davey
Rachel A
RA
D000375:Aging; D000818:Animals; D001483:Base Sequence; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D001947:Breeding; D005091:Exons / Q000235:genetics; D008159:Lumbar Vertebrae / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010641:Phenotype; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion
D011944:Receptors, Androgen