Estrogens Maintain Bone Mass by Regulating Expression of Genes Controlling Function and Life Span in Mature Osteoclasts

Authors

  • Yuuki Imai,

    1. Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
    2. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
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  • Ming-Young Youn,

    1. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
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  • Shino Kondoh,

    1. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
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  • Takashi Nakamura,

    1. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
    2. ERATO, Japan Science and Technology Agency, Saitama, Japan
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  • Alexander Kouzmenko,

    1. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
    2. ERATO, Japan Science and Technology Agency, Saitama, Japan
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  • Takahiro Matsumoto,

    1. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
    2. ERATO, Japan Science and Technology Agency, Saitama, Japan
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  • Ichiro Takada,

    1. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
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  • Kunio Takaoka,

    1. Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
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  • Shigeaki Kato

    1. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
    2. ERATO, Japan Science and Technology Agency, Saitama, Japan
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Address for correspondence: Shigeaki Kato, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Voice: 81-3-5841-8478; fax: 81-3-5841-8477. uskato@mail.ecc.u-tokyo.ac.jp

Abstract

Estrogens play a key role in regulation of bone mass and strength by controlling activity of bone-forming osteoblasts and bone-resorbing osteoclasts. Cellular effects of estrogens are mediated predominantly by the action of estrogen receptor alpha (ERα). In earlier studies, ablation of the ERα gene in mice did not result in osteoporotic phenotypes due to systemic endocrine disturbance and compensatory effects of elevated levels of testosterone. Despite the relatively well-established effects in osteoblasts, little is known about the direct action of estrogen in osteoclasts. Development in the last decade of more sophisticated genetic manipulation approaches opened new possibilities to explore cell-specific roles of nuclear receptors in bone tissue. Recently, we have generated osteoclast-specific ERα gene knockout mice and shown that in vivo estrogens directly regulate the life span of mature osteoclasts by inducing the expression of pro-apoptotic Fas ligand (FasL). Inhibitory effects of estrogens on osteoclast function were further studied in vitro. We observed sufficiently detectable ERα expression in osteoclasts differentiating from primary bone marrow cells or RAW264 cells, although levels of ERα were decreasing during progression of the differentiation into mature osteoclasts. Treatment with estrogens led to reduction in expression of osteoclast-specific genes controlling bone resorption activity. However, estrogens did not affect the size of multinucleated osteoclasts or number of nuclei in a mature osteoclast. In conclusion, in osteoclasts, estrogens function to inhibit bone resorption activity and vitality rather than differentiation.

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