Estrogen Prevents Bone Loss via Estrogen Receptor α and Induction of Fas Ligand in Osteoclasts

Takashi Nakamura, Yuuki Imai, Takahiro Matsumoto, Shingo Sato, Kazusane Takeuchi, Katsuhide Igarashi, Yoshifumi Harada, Yoshiaki Azuma, Andree Krust, Yoko Yamamoto, Hiroshi Nishina, Shu Takeda, Hiroshi Takayanagi, Daniel Metzger, Jun Kanno, Kunio Takaoka, T. John Martin, Pierre Chambon, Shigeaki Kato

Research output: Contribution to journalArticle

610 Citations (Scopus)

Abstract

Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor α (ERα) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERα in differentiated osteoclasts (ERαΔOc/ΔOc) and found that ERαΔOc/ΔOc females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERαΔOc/ΔOc mice. The expression of ERα was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.

Original languageEnglish
Pages (from-to)811-823
Number of pages13
JournalCell
Volume130
Issue number5
DOIs
Publication statusPublished - 2007 Sep 7
Externally publishedYes

Keywords

  • DEVBIO
  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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  • Cite this

    Nakamura, T., Imai, Y., Matsumoto, T., Sato, S., Takeuchi, K., Igarashi, K., Harada, Y., Azuma, Y., Krust, A., Yamamoto, Y., Nishina, H., Takeda, S., Takayanagi, H., Metzger, D., Kanno, J., Takaoka, K., Martin, T. J., Chambon, P., & Kato, S. (2007). Estrogen Prevents Bone Loss via Estrogen Receptor α and Induction of Fas Ligand in Osteoclasts. Cell, 130(5), 811-823. https://doi.org/10.1016/j.cell.2007.07.025