New insights into a Potential therapeutic agent for Postmenopausal Osteoporosis: Focus on the novel Effects of Unkeito

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  • Fang Ke
    Department of Hygiene and Public Health, Kansai Medical University
  • Murakami Yuki
    Department of Hygiene and Public Health, Kansai Medical University
  • Kanda Seiji
    Department of Hygiene and Public Health, Kansai Medical University
  • Shimono Takaki
    Department of Hygiene and Public Health, Kansai Medical University
  • Dang Anh Tuan
    Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  • Ono Mitsuaki
    Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Department of Oral Rehabilitation and Implantology, Okayama University Hospital
  • Nishiyama Toshimasa
    Department of Hygiene and Public Health, Kansai Medical University

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  • 温経湯による閉経後骨粗鬆症治療のための新たな展望：エストロゲン様作用と破骨細胞分化の調節
  • オンケイ ユ ニ ヨル ヘイケイ ゴ コツソショウショウ チリョウ ノ タメ ノ アラタ ナ テンボウ : エストロゲン ヨウ サヨウ ト ハ コツ サイボウ ブンカ ノ チョウセツ

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Abstract

<p>Osteoporosis is a common bone disorder, particularly prevalent in postmenopausal women. While previous therapeutic ­targets for osteoporosis are increasing bone mass, it is crucial to develop effective therapies that improve both bone quantity and quality, normalize bone metabolism, and ultimately reduce the risk of fractures. Recently, various traditional Kampo medicine formulations have shown efficacy in maintaining bone health, although their underlying mechanisms remain unclear. In this study, we focused on a commonly used traditional Kampo medicine for treating menopausal symptoms, especially Unkeito (UKT). We investigated the effects of UKT on osteoclast differentiation induced by the receptor activator of nuclear factor-kappaB ligand (RANKL), a key factor in osteoclast formation, aiming to elucidate the mechanism of UKT. Among the various Kampo medicines screened, UKT exhibited the most potent inhibitory effect on osteoclastogenesis. UKT inhibited the essential transcription factor NFATc1 (the nuclear factor of activated T cells 1), which is crucial for the early differentiation of osteoclast. Additionally, it suppressed the nuclear translocation of NF-κB, an upstream signal of NFATc1, while activating the Blimp1-Bcl6 signaling pathway, which inhibits NFATc1. Ultimately, we revealed that UKT inhibits upstream of NFATc1 signal pathway, thereby suppressing the differentiation and maturation of osteoclast. Additionally, we demonstrated that UKT induces apoptosis in mononuclear osteoclasts through the activation of caspase-3. This study is the first to clarify that UKT suppresses RANKL-mediated osteoclastogenesis through the Blimp1–Bcl6 and NF-κB signaling pathways, while enhancing mononuclear osteoclast apoptosis. These findings suggest that UKT has the potential to be an effective therapeutic agent for postmenopausal osteoporosis. This article provides an overview of our research findings.</p>

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