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

Abstract

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 μmversus 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