Estrogens maintain bone mass by regulating expression of genes controlling function and life span in mature osteoclasts

Yuuki Imai, Ming Young Youn, Shino Kondoh, Takashi Nakamura, Alexander Kouzmenko, Takahiro Matsumoto, Ichiro Takada, Kunio Takaoka, Shigeaki Kato

Research output: Contribution to journalReview articlepeer-review

84 Citations (Scopus)


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.

Original languageEnglish
JournalAnnals of the New York Academy of Sciences
Issue numberSUPPL. 1
Publication statusPublished - 2009 Sept
Externally publishedYes


  • bone
  • estrogen receptor
  • osteoclast

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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