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Effects of Sex Steroid Receptor Specificity in the Regulation of Skeletal Metabolism

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Abstract

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 (ERα), androgen receptor (AR, mutant tfm), or both, and determine if ERα and AR alter osteoblast differentiation and/or PTH response in vitro. Loss of ERα resulted in increased long bone length in females, but reduced length in males, suggesting loss of ERα 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 ERα. Loss of AR and/or ERα resulted in a reduction in femoral bone mineral density (BMD) compared to male wildtype (WT) mice, suggesting tfm mice follow the female sex for BMD. In males or tfm mice, but not females, loss of AR and/or ERα 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 ERα 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 ERα 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 ERα and/or AR results in increased osteoblast sensitivity to PTH and may explain actions of PTH noted in hypogonadal humans.

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Acknowledgments

This work was partially supported by the National Institutes of Health (DK 56356), the Nathan Shock Center for the Basic Biology of Aging (NIA AG 13283), the Center for Craniofacial Regeneration and TÜBITAK (The Scientific and Technical Research Council of Turkey) Integrated Ph.D. Program. The authors express sincere appreciation to A. Krüst, and P. Chambon for providing the ERα−/− mice for these studies.

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Authors and Affiliations

  1. Department of Periodontics/Prevention/Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA

    Tolga F. Tözüm, Mark E. Oppenlander, Amy J. Koh-Paige & Laurie K. McCauley

  2. Department of Periodontology, Faculty of Dentistry, Hacettepe University, Ankara, Turkey

    Tolga F. Tözüm

  3. Department of Human Genetics, Medical School, University of Michigan, Ann Arbor, Michigan, USA

    Mark E. Oppenlander & Diane M. Robins

  4. Department of Pathology, Medical School, University of Michigan, Ann Arbor, Michigan, USA

    Laurie K. McCauley

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  1. Tolga F. Tözüm
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Correspondence to Laurie K. McCauley.

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Tözüm, T.F., Oppenlander, M.E., Koh-Paige, A.J. et al. Effects of Sex Steroid Receptor Specificity in the Regulation of Skeletal Metabolism. Calcif Tissue Int 75, 60–70 (2004). https://doi.org/10.1007/s00223-004-0119-8

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