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 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 < .001), trabecular thickness (p = .05), and trabecular separation (p < .01) to such a great extent that differences between XXY and XY mice were undetectable. In conclusion, XXY mice replicate many features of human Klinefelter syndrome and therefore are a useful model for studying bone. Testosterone deficiency does not explain the bone phenotype because testosterone-replaced XXY mice show reduced bone volume despite similar blood testosterone levels. © 2010 American Society for Bone and Mineral Research.
Highlights
Chromosomal dysjunction occurs during meiosis in all mammalian species and sometimes can result in aneuploidal live-birth offspring
The features and consequences of human Klinefelter syndrome (KS) have been identified without ascertainment bias through national population-based studies that link cytogenetic diagnoses with mortality registries or hospital admissions.[10,11,12,13] These studies confirm an increased risk of osteoporosis[13] and death from femoral fracture,(11) in later life.[14] it has long been assumed that osteoporosis and increased fracture risk occur owing to coexisting androgen deficiency rather than KS per se, and many studies have not separated KS from other causes of hypogonadism analytically
Testosterone therapy administered to men with primary hypogonadism generally improves bone mineral density (BMD),(17) but normalization of bone may be incomplete in some men with KS,(18,19) especially if therapy is suboptimal.[20] men with KS exhibit other bone and joint abnormalities (ie, premature fusion and excessive calcification of coronal sutures,(21) abnormal joint development,(22) and osteoarthritis[13]) that are not typically observed in other hypogonadal men
Summary
Chromosomal dysjunction occurs during meiosis in all mammalian species and sometimes can result in aneuploidal live-birth offspring. The features and consequences of human KS have been identified without ascertainment bias through national population-based studies that link cytogenetic diagnoses with mortality registries or hospital admissions.[10,11,12,13] These studies confirm an increased risk of osteoporosis[13] and death from femoral fracture,(11) in later life.[14] it has long been assumed that osteoporosis and increased fracture risk occur owing to coexisting androgen deficiency rather than KS per se, and many studies have not separated KS from other causes of hypogonadism analytically Consistent with this hypothesis, both higher concurrent systemic testosterone concentrations[15] and shorter androgen receptor polyalanine length (which results in greater androgen receptor transactivation)(16) are associated with higher bone mineral density (BMD) in men. The purpose of this study was to characterize bone architecture, volume, and turnover in intact, castrated, and simultaneously castrated and testosteronereplaced XXY mice by static and dynamic histomorphometry, micro–computed tomography (mCT), and dual-energy X-ray absorptiometry (DXA)
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