Medicine (Austin & Northern Health) - Research Publications
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ItemCommon variants in the region around Osterix are associated with bone mineral density and growth in childhood(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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ItemStructural basis of growth-related gain and age-related loss of bone strength(OXFORD UNIV PRESS, 2008-07)If bone strength was the only requirement of skeleton, it could be achieved with bulk, but bone must also be light. During growth, bone modelling and remodelling optimize strength, by depositing bone where it is needed, and minimize mass, by removing it from where it is not. The population variance in bone traits is established before puberty and the position of an individual's bone size and mass tracks in the percentile of origin. Larger cross-sections have a comparably larger marrow cavity, which results in a lower volumetric BMD (vBMD), thereby avoiding bulk. Excavation of a marrow cavity thus minimizes mass and shifts the cortex radially, increasing rigidity. Smaller cross-sections are assembled by excavating a smaller marrow cavity leaving a relatively thicker cortex producing a higher vBMD, avoiding the fragility of slenderness. Variation in cellular activity around the periosteal and endocortical envelopes fashions the diverse shapes of adjacent cross-sections. Advancing age is associated with a decline in periosteal bone formation, a decline in the volume of bone formed by each basic multicellular unit (BMU), continued resorption by each BMU, and high remodelling after menopause. Bone loss in young adulthood has modest structural and biomechanical consequences because the negative BMU balance is driven by reduced bone formation, remodelling is slow and periosteal apposition continues shifting the thinned cortex radially. But after the menopause, increased remodelling, worsening negative BMU balance and a decline in periosteal apposition accelerate cortical thinning and porosity, trabecular thinning and loss of connectivity. Interstitial bone, unexposed to surface remodelling becomes more densely mineralized, has few osteocytes and greater collagen cross-linking, and accumulates microdamage. These changes produce the material and structural abnormalities responsible for bone fragility.
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ItemNo Preview AvailableMineralization and Bone Resorption Are Regulated by the Androgen Receptor in Male Mice(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.