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

Susan A. Krum, Gustavo A. Miranda-Carboni, Peter V. Hauschka, Jason S. Carroll, Timothy F Lane, Leonard P. Freedman, Myles Brown*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

234 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)535-545
Number of pages11
JournalEMBO Journal
Volume27
Issue number3
DOIs
StatePublished - Feb 6 2008

Keywords

  • Bone
  • Estrogen
  • Fas ligand
  • Osteoblast
  • Osteoclast

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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