Elucidation of essential common molecular mechanisms that control postmenopausal osteoporosis and weight gain and development of therapeutic strategies

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H03108
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Kyushu University
• Principal Investigator: Jimi Eijiro 九州大学, 歯学研究院, 教授 (40276598)
• Co-Investigator(Kenkyū-buntansha): 片桐 岳信 埼玉医科大学, 医学部, 教授 (80245802) ; 川端 由子 九州大学, 歯学研究院, 助教 (40906830)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: NF-κB / 閉経後骨粗鬆症 / 肥満 / エストロゲン

Outline of Final Research Achievements

Postmenopausal women experience bone loss and weight gain via NF-κB activation. We examined the role of NF-κB in bone and energy metabolism following menopause. NF-κB reporter mice, which can be used to measure NF-κB activation in vivo, were ovariectomized (OVX) and the luminescence intensity after OVX increased in the epiphyses of the long bones and WAT, but not in the other tissues. OVX was performed on wild-type (WT) and p65 (S534A) mutant knock-in mice, in which enhances the transcriptional activity of NF-κB. Compared to WT mice, weight gain with worsening glucose tolerance and trabecular bone loss due to the suppression of bone formation and increase in bone marrow adipocytes were observed in the S534A KI-OVX group. Disulfiram, an anti-alcoholic drug, suppressed OVX-induced activation of NF-κB and also suppressed weight gain and bone loss. Taken together, activation of NF-κB in the epiphyses of long bones and WAT after OVX regulates post-OVX weight gain and bone loss.

Free Research Field

骨・エネルギー代謝研究

Academic Significance and Societal Importance of the Research Achievements

閉経後の女性の骨量の減少は運動機能の低下、また体重増加は生活習慣病やがんの発症と関連する。我々は閉経後骨粗鬆症モデルである卵巣摘出術（OVX）を用いて、OVX後１週間で骨端部と白色脂肪組織で骨代謝やエネルギー代謝に重要なNF-κBが活性化されること、NF-κBの活性化が亢進したマウスではOVX後の骨量減少と体重増加が亢進することを明らかにした。さらに、NF-κBの活性化の抑制効果を持つ抗アルコール薬であるジスルフィラム (DSF)の投与が、OVX後の骨量減少と体重増加を抑制することを明らかにした。以上の結果は、NF-κBが閉経後の骨量減少と体重増加の新たな治療標的になる可能性を示唆する。