Effects of sex steroid receptor specificity in the regulation of skeletal metabolism

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Tozum T., Oppenlander M., Koh-Paige A., Robins D., McCauley L.

CALCIFIED TISSUE INTERNATIONAL, vol.75, no.1, pp.60-70, 2004 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 75 Issue: 1
  • Publication Date: 2004
  • Doi Number: 10.1007/s00223-004-0119-8
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.60-70
  • Hacettepe University Affiliated: No


The interaction between estrogens and androgens, with their protective effects in bone, and parathyroid hormone (PTH), a calcitropic peptide hormone, is complex but may be better understood with murine models. The purpose of this study was to characterize skeletal phenotypes of mice deficient in estrogen receptor alpha (ERalpha), androgen receptor (AR, mutant tfm), or both, and determine if ERalpha and AR alter osteoblast differentiation and/or PTH response in vitro. Loss of ERalpha resulted in increased long bone length in females, but reduced length in males, suggesting loss of ERalpha reversed sex steroid-dependent skeletal dimorphism. The AR deficient tfm mice (genetically male but phenotypically female) had the longest bones and, similar to males, lengths were reduced with loss of ERalpha. Loss of AR and/or ERalpha resulted in a reduction in femoral bone mineral density (BMD) compared to male wildtype (WT) mice, suggesting fin mice follow the female sex for BNID. In males or tfm mice, but not females, loss of AR and/or ERalpha. caused a reduction in cortical width of the tibia compared to male WT mice. Reduced trabecular bone was found in tibiae of female and tfm mice versus male littermates, suggesting that tfm mice follow the female sex for trabecular bone but loss of ERalpha did not alter trabecular bone levels. Primary calvarial osteoblasts of male WT mice were less responsive to PTH stimulation of cAMP than all other genotypes, suggesting the female chromosomal sex and/ or loss of ERalpha or AR results in increased sensitivity to PTH. In conclusion, tfm mice follow the male pattern of long bone development, but imitate females in bone density and trabecular bone. Loss of ERalpha and/or AR results in increased osteoblast sensitivity to PTH and may explain actions of PTH noted in hypogonadal humans.