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Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice.

ABSTRACT: Ovariectomy in young, growing rodents results in decreased trabecular bone mineral density (BMD) and increased radial growth of the cortical bone. Both of these effects are reversed by treatment with estrogen. The aim of the present study was to determine the physiological role of estrogen receptor-beta (ERbeta) on bone structure and bone mineral content (BMC). The BMC was increased in adult (11 weeks old), but not prepubertal (4 weeks old), female ERbeta(-/-) mice compared with wild-type (WT) mice. This increase in BMC in females was not due to increased trabecular BMD, but to an increased cross-sectional cortical bone area associated with a radial bone growth. Male ERbeta(-/-) mice displayed no bone abnormalities compared with WT mice. Ovariectomy decreased the trabecular BMD to the same extent in adult female ERbeta(-/-) mice as in WT mice. The expression levels of osteoblast-associated genes - alpha1(I) collagen, alkaline phosphatase, and osteocalcin mRNAs - were elevated in bone from adult ERbeta(-/-) females compared with WT mice. These observations provide a possible explanation for the increased radial bone growth seen in female mutants, suggesting a repressive function for ERbeta in the regulation of bone growth during female adolescence. In summary, ERbeta is essential for the pubertal feminization of the cortical bone in female mice but is not required for the protective effect of estrogens on trabecular BMD.

SUBMITTER: Windahl SH

PROVIDER: S-EPMC408552 | biostudies-literature | 1999 Oct

REPOSITORIES: biostudies-literature

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Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice.

Windahl S H SH Vidal O O Andersson G G Gustafsson J A JA Ohlsson C C

The Journal of clinical investigation 19991001 7

Ovariectomy in young, growing rodents results in decreased trabecular bone mineral density (BMD) and increased radial growth of the cortical bone. Both of these effects are reversed by treatment with estrogen. The aim of the present study was to determine the physiological role of estrogen receptor-beta (ERbeta) on bone structure and bone mineral content (BMC). The BMC was increased in adult (11 weeks old), but not prepubertal (4 weeks old), female ERbeta(-/-) mice compared with wild-type (WT) m ...[more]

PMID: 10510330

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Project description:Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n?=?5,878) followed by replication (n?=?1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p?=?3.6×10?¹?; LOC285735, rs271170, p?=?2.7×10?¹²; OPG, rs7839059, p?=?1.2×10?¹?; and ESR1/C6orf97, rs6909279, p?=?1.1×10??). The trabecular vBMD GWA meta-analysis (n?=?2,500) followed by replication (n?=?1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p?=?1.9×10??). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n?=?729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.

Dataset Information

Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice.

Publications

Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice.

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