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

doi:10.1016/j.cell.2007.07.025

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 journal › Article › peer-review

785 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 (ERα^ΔOc/ΔOc) and found that ERα^ΔOc/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 ERα^ΔOc/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 language	English
Pages (from-to)	811-823
Number of pages	13
Journal	Cell
Volume	130
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2007.07.025
Publication status	Published - 2007 Sept 7
Externally published	Yes

Keywords

DEVBIO
HUMDISEASE
SIGNALING

ASJC Scopus subject areas

Cell Biology
Molecular Biology

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10.1016/j.cell.2007.07.025

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

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, TJ, Chambon, P & Kato, S 2007, 'Estrogen Prevents Bone Loss via Estrogen Receptor α and Induction of Fas Ligand in Osteoclasts', Cell, vol. 130, no. 5, pp. 811-823. https://doi.org/10.1016/j.cell.2007.07.025

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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.",

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

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AU - Nakamura, Takashi

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AU - Sato, Shingo

AU - Takeuchi, Kazusane

AU - Igarashi, Katsuhide

AU - Harada, Yoshifumi

AU - Azuma, Yoshiaki

AU - Krust, Andree

AU - Yamamoto, Yoko

AU - Nishina, Hiroshi

AU - Takeda, Shu

AU - Takayanagi, Hiroshi

AU - Metzger, Daniel

AU - Kanno, Jun

AU - Takaoka, Kunio

AU - Martin, T. John

AU - Chambon, Pierre

AU - Kato, Shigeaki

PY - 2007/9/7

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N2 - 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.

AB - 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.

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

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Keywords

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