Medicine (Austin & Northern Health) - Research Publications

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Start date: 2009 × End date: 2009 × Author: Seeman, Ego ×

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    Common variants in the region around Osterix are associated with bone mineral density and growth in childhood
    Timpson, NJ ; Tobias, JH ; Richards, JB ; Soranzo, N ; Duncan, EL ; Sims, A-M ; Whittaker, P ; Kumanduri, V ; Zhai, G ; Glaser, B ; Eisman, J ; Jones, G ; Nicholson, G ; Prince, R ; Seeman, E ; Spector, TD ; Brown, MA ; Peltonen, L ; Smith, GD ; Deloukas, P ; Evans, DM (OXFORD UNIV PRESS, 2009-04-15)
    Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 x 10(-4); Australia: P = 3.7 x 10(-4)). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 x 10(-11)). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 x 10(-5)). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.
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    Mineralization and Bone Resorption Are Regulated by the Androgen Receptor in Male Mice
    Chiang, C ; Chiu, M ; Moore, AJ ; Anderson, PH ; Zadeh, AG ; McManus, JF ; Ma, C ; Seeman, E ; Clemens, TL ; Morris, HA ; Zajac, JD ; Davey, RA (WILEY, 2009-04)
    Androgens play a key role in skeletal growth and bone maintenance; however, their mechanism of action remains unclear. To address this, we selectively deleted the androgen receptor (AR) in terminally differentiated, mineralizing osteoblasts using the Cre/loxP system in mice (osteocalcin-Cre AR knockouts [mOBL-ARKOs]). Male mOBL-ARKOs had decreased femoral trabecular bone volume compared with littermate controls because of a reduction in trabecular number at 6, 12, and 24 wk of age, indicative of increased bone resorption. The effects of AR inactivation in mineralizing osteoblasts was most marked in the young mutant mice at 6 wk of age when rates of bone turnover are high, with a 35% reduction in trabecular bone volume, decreased cortical thickness, and abnormalities in the mineralization of bone matrix, characterized by increased unmineralized bone matrix and a decrease in the amount of mineralizing surface. This impairment in bone architecture in the mOBL-ARKOs persisted throughout adulthood despite an unexpected compensatory increase in osteoblast activity. Our findings show that androgens act through the AR in mineralizing osteoblasts to maintain bone by regulating bone resorption and the coordination of bone matrix synthesis and mineralization, and that this action is most important during times of bone accrual and high rates of bone remodeling.