Genetic and hormonal control of bone volume, architecture, and remodeling in XXY mice

Klinefelter syndrome is the most common chromosomal aneuploidy in men (XXY karyotype, 1 in 600 live births) and results in testicular (infertility and androgen deficiency) and nontesticular (cognitive impairment and osteoporosis) deficits. The extent to which skeletal changes are due to testosterone...

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Bibliographic Details
Published in:Journal of bone and mineral research 2010-10, Vol.25 (10), p.2148-2154
Main Authors: Liu, Peter Y, Kalak, Robert, Lue, YanHe, Jia, Yue, Erkkila, Krista, Zhou, Hong, Seibel, Markus J, Wang, Christina, Swerdloff, Ronald S, Dunstan, Colin R
Format: Article
Language:English
Subjects:
aneuploidy
Animals
Biological and medical sciences
bone
Bone Remodeling
Chromosomes, Human, X - genetics
Disease Models, Animal
Fundamental and applied biological sciences. Psychology
Karyotyping
klinefelter syndrome
Klinefelter Syndrome - genetics
Klinefelter Syndrome - pathology
Klinefelter Syndrome - physiopathology
Male
Mice
Orchiectomy
Original
osteoporosis
Radioimmunoassay
Sex Chromosome Aberrations
Skeleton and joints
testosterone
Testosterone - blood
Testosterone - physiology
Trisomy - genetics
Trisomy - pathology
Trisomy - physiopathology
Vertebrates: osteoarticular system, musculoskeletal system
XXY
x‐inactivation
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Summary:Klinefelter syndrome is the most common chromosomal aneuploidy in men (XXY karyotype, 1 in 600 live births) and results in testicular (infertility and androgen deficiency) and nontesticular (cognitive impairment and osteoporosis) deficits. The extent to which skeletal changes are due to testosterone deficiency or arise directly from gene overdosage cannot be determined easily in humans. To answer this, we generated XXY mice through a four‐generation breeding scheme. Eight intact XXY and 9 XY littermate controls and 8 castrated XXY mice and 8 castrated XY littermate controls were euthanized at 1 year of age. Castration occurred 6 months prior to killing. A third group of 9 XXY and 11 XY littermates were castrated and simultaneously implanted with a 1‐cm Silastic testosterone capsule 8 weeks prior to sacrifice. Tibias were harvested from all three groups and examined by micro–computed tomography and histomorphometry. Blood testosterone concentration was assayed by radioimmunoassay. Compared with intact XY controls, intact androgen‐deficient XXY mice had lower bone volume (6.8% ± 1.2% versus8.8% ± 1.7%, mean ± SD, p = .01) and thinner trabeculae (50 ± 4 µm versus 57 ± 5 µm, p = .007). Trabecular separation (270 ± 20 µm versus 270 ± 20 µm) or osteoclast number relative to bone surface (2.4 ± 1.0/mm2 versus 2.7 ± 1.5/mm2) did not differ significantly. Testosterone‐replaced XXY mice continued to show lower bone volume (5.5% ± 2.4% versus 8.1% ± 3.5%, p = .026). They also exhibited greater trabecular separation (380 ± 69 µm versus 324 ± 62 µm, p = .040) but equivalent blood testosterone concentrations (6.3 ± 1.8 ng/mL versus 8.2 ± 4.2 ng/mL, p = .28) compared with testosterone‐replaced XY littermates. In contrast, castration alone drastically decreased bone volume (p 
ISSN:0884-0431
1523-4681
DOI:10.1002/jbmr.104