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

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

Research output: Contribution to journalArticle

195 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Fas Ligand Protein
Osteoblasts
Osteoclasts
Bone
Estrogens
Bone and Bones
Apoptosis
Osteoporosis
Selective Estrogen Receptor Modulators
Estrogen Receptor alpha
Tamoxifen
Menopause
Up-Regulation
Genes
Hormones

All Science Journal Classification (ASJC) codes

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

Cite this

Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. / Miranda, Susan; Miranda-Carboni, Gustavo; Hauschka, Peter V.; Carroll, Jason S.; Lane, Timothy F.; Freedman, Leonard P.; Brown, Myles.

In: EMBO Journal, Vol. 27, No. 3, 06.02.2008, p. 535-545.

Research output: Contribution to journalArticle

Miranda, Susan ; Miranda-Carboni, Gustavo ; Hauschka, Peter V. ; Carroll, Jason S. ; Lane, Timothy F. ; Freedman, Leonard P. ; Brown, Myles. / Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. In: EMBO Journal. 2008 ; Vol. 27, No. 3. pp. 535-545.
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