Our previous study showed that estrogen can induce mitochondrial adenosine triphosphate (ATP) synthesis-associated gene expressions and osteoblast maturation. Genistein, a phytoestrogenic isoflavone that is widely found in various foods and traditional herb products, is beneficial for osteogenesis by selectively triggering estrogen receptor alpha (ERα) expression. In this study, we further investigated the mechanisms of genistein-induced energy production and osteoblast activation. Exposure of rat calvarial osteoblasts and human U-2 OS cells to genistein triggered osteoblast activation without affecting cell survival. Treatment with genistein time-dependently induced ERα mRNA and protein expressions in rat calvarial osteoblasts. Analyses by confocal microscopy and immunoblotting showed that genistein stimulated translocation of ERα from the cytoplasm to mitochondria. Subsequently, expressions of mitochondrial cytochrome c oxidase (COX) I and II mRNAs and proteins in primary rat osteoblasts were induced after exposure to genistein. Knocking-down ERα concurrently inhibited genistein-induced COX I and II mRNA expressions. In addition, mitochondrial complex enzyme activities, the mitochondrial membrane potential, and cellular ATP levels in rat calvarial osteoblasts were time-dependently augmented by genistein. Suppressing ERα expression instantaneously lowered genistein-induced enhancements of mitochondrial energy production and osteoblast activation. Effects of genistein on ERα translocation, COX I and II mRNA expressions, ATP synthesis, and osteoblast activation were further confirmed in human U-2 OS cells. This study showed that genistein can stimulate energy production and consequent osteoblast activation via inducing ERα-mediated mitochondrial ATP synthesis-linked gene expressions.

Original languageEnglish
Pages (from-to)901-923
Number of pages23
JournalAmerican Journal of Chinese Medicine
Issue number4
Publication statusAccepted/In press - 2021


  • Energy Production
  • Estrogen Receptor Alpha
  • Genistein
  • Mitochondrial Gene Expression
  • Osteoblast Maturation

ASJC Scopus subject areas

  • Complementary and alternative medicine


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