Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival

Authors

  • Susan A Krum,

    1. Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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  • Gustavo A Miranda-Carboni,

    1. Departments of Ob-Gyn and Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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  • Peter V Hauschka,

    1. Department of Orthopaedic Surgery, Children's Hospital and Harvard Medical School, Boston, MA, USA
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  • Jason S Carroll,

    1. Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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    • Present address: Cancer Research UK, Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, UK
  • Timothy F Lane,

    1. Departments of Ob-Gyn and Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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  • Leonard P Freedman,

    1. Department of Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, PA, USA
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  • Myles Brown

    Corresponding author
    1. Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
    • Corresponding author. Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, D730, Boston, MA 02115, USA. Tel.: +1 617 632 3948; Fax: +1 617 632 5417; E-mail: myles_brown@dfci.harvard.edu

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Abstract

Estrogen deficiency in menopause is a major cause of osteoporosis in women. Estrogen acts to maintain the appropriate ratio between bone-forming osteoblasts and bone-resorbing osteoclasts in part through the induction of osteoclast apoptosis. Recent studies have suggested a role for Fas ligand (FasL) in estrogen-induced osteoclast apoptosis by an autocrine mechanism involving osteoclasts alone. In contrast, we describe a paracrine mechanism in which estrogen affects osteoclast survival through the upregulation of FasL in osteoblasts (and not osteoclasts) leading to the apoptosis of pre-osteoclasts. We have characterized a cell-type-specific hormone-inducible enhancer located 86 kb downstream of the FasL gene as the target of estrogen receptor-alpha induction of FasL expression in osteoblasts. In addition, tamoxifen and raloxifene, two selective estrogen receptor modulators that have protective effects in bone, induce apoptosis in pre-osteoclasts by the same osteoblast-dependent mechanism. These results demonstrate that estrogen protects bone by inducing a paracrine signal originating in osteoblasts leading to the death of pre-osteoclasts and offer an important new target for the prevention and treatment of osteoporosis.

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