Regulation of bone homeostasis by sex hormones and hypoxia responsive molecules

• Project/Area Number: 15H04963
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: Miyamoto Takeshi 慶應義塾大学, 医学部(信濃町), 特任准教授 (70383768)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 骨粗鬆症 / 整形外科 / 破骨細胞 / 性ホルモン / トランスレーショナルリサーチ

Outline of Final Research Achievements

Estrogen deficiency due to menopause causes activation of osteoclastic bone-resorption leading to osteoporosis development. We found that HIF1α, a hypoxia responsive transcription factor, was expressed in osteoclasts under an estrogen deficient condition. Then, we screened and identified several HIF1α inhibitors as candidate therapeutic agents for postmenopausal osteoporosis treatment (published in 2016). We also found that HIF1α was expressed in osteoclasts in male osteoporosis model mice (published in 2016). We demonstrated that reduction of bone mass in male osteoporosis model mice could be completely abrogated by administration of the HIF1α inhibiting agents, all of which were identified by us (published in 2017).

Research Products

• [Journal Article] Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head (2017)
  • Author(s): Sakamoto Y, Yamamoto T, Sugano N, Takahashi D, Watanabe T, Atsumi T, Nakamura J, Hasegawa Y, Akashi K, Narita I, Miyamoto T, Takeuchi T, Ikari K, Amano K, Fujie A, Kubo T, Tada Y, Kaneuji A, Nakamura H, Miyamura T, Kabata T, Yamaji K, Okawa T, Sudo A, Ohzono K, Tanaka Y, Yasunaga Y, Matsuda S, Imai Y
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 15035-15035
  • DOI: 10.1038/s41598-017-14778-y
  • NAID: 120006817606
  • Peer Reviewed / Open Access
• [Journal Article] The effect of switching from teriparatide to anti-RANKL antibody on cancellous and cortical bone in ovariectomized mice. (2017)
  • Author(s): Omiya T, Hirose J, Hasegawa T, Amizuka N, Omata Y, Izawa N, Yasuda H, Kadono Y, Matsumoto M, Nakamura M, Miyamoto T, Tanaka S.
  • Journal Title: Bone Volume: 107 Pages: 18-26
  • DOI: 10.1016/j.bone.2017.10.021
  • Peer Reviewed
• [Journal Article] Stat3 as a potential therapeutic target for rheumatoid arthritis. (2017)
  • Author(s): Oike T, Sato Y, Kobayashi T, Miyamoto K, Nakamura S, Kaneko Y, Kobayashi S, Harato K, Saya H, Matsumoto M, Nakamura M, Niki Y, Miyamoto T.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 10965-10965
  • DOI: 10.1038/s41598-017-11233-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions. (2017)
  • Author(s): Watanabe R, Fujita N, Sato Y, Kobayashi T, Morita M, Oike T, Miyamoto K, Kuro-O M, Michigami T, Fukumoto S, Tsuji T, Toyama Y, Nakamura M, Matsumoto M, Miyamoto T.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 7786-7786
  • DOI: 10.1038/s41598-017-07341-2
  • NAID: 120006535028
  • Peer Reviewed / Open Access
• [Journal Article] Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1. (2017)
  • Author(s): Nakamura S, Koyama T, Izawa N, Nomura S, Fujita T, Omata Y, Minami T, Matsumoto M, Nakamura M, Fujita-Jimbo E, Momoi T, Miyamoto T, Aburatani H, Tanaka S.
  • Journal Title: PLoS One Volume: 12 Issue: 4 Pages: e0175632-e0175632
  • DOI: 10.1371/journal.pone.0175632
  • Peer Reviewed / Open Access
• [Journal Article] Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis (2017)
  • Author(s): Morita M, Iwasaki R, Sato Y, Kobayashi T, Watanabe R, Oike T, Nakamura S, Keneko Y, Miyamoto K, Ishihara K, Iwakura Y, Ishii K, Matsumoto M, Nakamura M, Kawana H, Nakagawa T, Miyamoto T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 46322-46322
  • DOI: 10.1038/srep46322
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The nicotinic acetylcholine receptor α7 subunit is an essential negative regulator of bone mass. (2017)
  • Author(s): Mito K, Sato Y, Kobayashi T, Miyamoto K, Nitta E, Iwama A, Matsumoto M, Nakamura M, Sato K, Miyamoto T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 45597-45597
  • DOI: 10.1038/srep45597
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A missense single nucleotide polymorphism in the ALDH2 gene, rs671, is associated with hip fracture. (2017)
  • Author(s): Takeshima K, Nishiwaki Y, Suda Y, Niki Y, Sato Y, Kobayashi T, Miyamoto K, Uchida H, Inokuchi W, Tsuji T, Funayama A, Nakamura M, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 428-428
  • DOI: 10.1038/s41598-017-00503-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A serum metabolomics-based profile in low bone mineral density postmenopausal women. (2017)
  • Author(s): Miyamoto T, Hirayama A, Sato Y, Koboyashi T, Katsuyama E, Kanagawa H, Miyamoto H, Mori T, Yoshida S, Fujie A, Morita M, Watanabe R, Tando T, Miyamoto K, Tsuji T, Funayama A, Nakamura M, Matsumoto M, Soga T, Tomita M, Toyama Y.
  • Journal Title: Bone Volume: 95 Pages: 1-4
  • DOI: 10.1016/j.bone.2016.10.027
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Selective estrogen receptor modulators and the vitamin D analogue eldecalcitol block bone loss in male osteoporosis (2017)
  • Author(s): Sato Y, Tando T, Morita M, Miyamoto K, Kobayashi T, Watanabe R, Oike T, Matsumoto M, Nakamura M, Miyamoto T.
  • Journal Title: Biochem Biophys Res Commun Volume: 482 Issue: 4 Pages: 1430-1436
  • DOI: 10.1016/j.bbrc.2016.12.053
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ibandronate concomitantly blocks immobilization-induced bone and muscle atrophy. (2016)
  • Author(s): Watanabe R, Fujita N, Takeda S, Sato Y, Kobayashi T, Morita M, Oike T, Miyamoto K, Matsumoto Y, Matsumoto M, Nakamura M, Miyamoto T.
  • Journal Title: Biochem Biophys Res Commun Volume: 480 Issue: 4 Pages: 662-668
  • DOI: 10.1016/j.bbrc.2016.10.112
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Selective Estrogen Receptor Modulators Suppress Hif1α Protein Accumulation in Mouse Osteoclasts (2016)
  • Author(s): Morita M, Sato Y, Iwasaki R, Kobayashi T, Watanabe R, Oike T, Miyamoto K, Toyama Y, Matsumoto M, Nakamura M, Kawana H, Nakagawa T, Miyamoto T.
  • Journal Title: PLoS One Volume: 11 Issue: 11 Pages: e0165922-e0165922
  • DOI: 10.1371/journal.pone.0165922
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Smad4 is required to inhibit osteoclastogenesis and maintain bone mass (2016)
  • Author(s): Morita M, Yoshida S, Iwasaki R, Yasui T, Sato Y, Kobayashi T, Watanabe R, Oike T, Miyamoto K, Takami M, Ozato K, Deng CX, Aburatani H, Tanaka S, Yoshimura A, Toyama Y, Matsumoto M, Nakamura M, Kawana H, Nakagawa T, Miyamoto T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 35221-35221
  • DOI: 10.1038/srep35221
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of Nedd9 as a TGF-β-Smad2/3 Target Gene Involved in RANKL-Induced Osteoclastogenesis by Comprehensive Analysis (2016)
  • Author(s): Omata Y, Nakamura S, Koyama T, Yasui T, Hirose J, Izawa N, Matsumoto T, Imai Y, Seo S, Kurokawa M, Tsutsumi S, Kadono Y, Morimoto C, Aburatani H, Miyamoto T, Tanaka S.
  • Journal Title: PLoS One. Volume: 11 Issue: 6 Pages: e0157992-e0157992
  • DOI: 10.1371/journal.pone.0157992
  • Peer Reviewed / Open Access
• [Journal Article] Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy (2016)
  • Author(s): Tando T, Hirayama A, Furukawa M, Sato Y, Kobayashi T, Funayama A, Kanaji A, Hao W, Watanabe R, Morita M, Oike T, Miyamoto K, Soga T, Nomura M, Yoshimura A, Tomita M, Matsumoto M, Nakamura M, Toyama Y, Miyamoto T
  • Journal Title: J Biol Chem Volume: 291 Issue: 23 Pages: 12184-94
  • DOI: 10.1074/jbc.m115.680579
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vitamin D Deficiency with High Intact PTH Levels is More Common in Younger than in Older Women: A Study of Women Aged 39–64 Years (2016)
  • Author(s): Miyamoto T, Katsuyama E, Kanagawa H, Fujie A, Miyamoto H, Yoshida S, Mori T, Miyamoto K, Sato Y, Kobayashi T, Nakamura M, Matsumoto M, Nishiwaki Y, Hirose H, Kanda T, Saito I, Toyama Y.
  • Journal Title: The Keio Journal of Medicine Volume: 65 Issue: 2 Pages: 33-38
  • DOI: 10.2302/kjm.2015-0010-OA
  • NAID: 130005158314
  • ISSN: 0022-9717, 1880-1293
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors. (2016)
  • Author(s): Kanagawa H, Masuyama R, Morita M, Sato Y, Niki Y, Kobayashi T, Katsuyama E, Fujie A, Hao W, Tando T, Watanabe R, Miyamoto K, Morioka H, Matsumoto M, Toyama Y, Saya H, Miyamoto T.
  • Journal Title: J Bone Miner Metab Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hif1α is required for osteoclast activation and bone loss in male osteoporosis. (2016)
  • Author(s): Tando T, Sato Y, Miyamoto K, Morita M, Kobayashi T, Funayama A, Kanaji A, Hao W, Watanabe R, Oike T, Nakamura M, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 2 Pages: 391-6
  • DOI: 10.1016/j.bbrc.2016.01.033
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Vitamin D Deficiency with High Intact PTH Levels isMore Common in Younger than in Older Women:A Study of Women Aged 39-64 Years (2016)
  • Author(s): Miyamoto T, Katsuyama E, Kanagawa H, Fujie A, Miyamoto H, Yoshida S, Mori T, Miyamoto K, Sato Y, Kobayashi T, Nakamura M, Matsumoto M, Nishiwaki Y, Hirose H, Kanda T, Saito I, Toyama Y
  • Journal Title: Keio J Med Volume: in press
  • Peer Reviewed
• [Journal Article] Smad2/3 are required for immobilization-induced skeletal muscle atrophy. (2016)
  • Author(s): Tando T, Hirayama A, Furukawa M, Sato Y, Kobayashi T, Funayama A, Kanaji A, Hao W, Watanabe R, Morita M, Oike T, Miyamoto K, Soga T, Nomura M, Yoshimura A, Tomita M, Matsumoto M, Nakamura M, Toyama Y, Miyamoto T.
  • Journal Title: J Biol Chem. Volume: in press
  • Peer Reviewed
• [Journal Article] Hyperglycaemia promotes Schwann cell de-differentiation and de-myelination via sorbitol accumulation and Igf1 downregulation. (2015)
  • Author(s): Hao W, Tashiro S, Hasegawa T, Sato Y, Kobayashi T, Tando T, Katsuyama E, Fujie A, Watanabe R, Morita M, Miyamoto K, Morioka H, Nakamura M, Matsumoto M, Amizuka N, Toyama Y, Miyamoto T.
  • Journal Title: J Biol Chem Volume: 290 Issue: 28 Pages: 17106-15
  • DOI: 10.1074/jbc.m114.631291
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mechanism Underlying Post-menopausal Osteoporosis: HIF1α is Required for Osteoclast Activation by Estrogen Deficiency (2015)
  • Author(s): Miyamoto T
  • Journal Title: The Keio Journal of Medicine Volume: 64 Issue: 3 Pages: 44-47
  • DOI: 10.2302/kjm.2015-0003-RE
  • NAID: 130005098947
  • ISSN: 0022-9717, 1880-1293
  • Peer Reviewed
• [Presentation] 破骨細胞の分化と免疫機能 (2017)
  • Author(s): 宮本健史
  • Organizer: 第３５回日本骨代謝学会学術集会
  • Invited
• [Presentation] 骨粗鬆症の基礎と臨床 (2017)
  • Author(s): 宮本健史
  • Organizer: 第４８回日本口腔外科学会教育研修会・口腔四学会合同研修会
  • Invited
• [Presentation] 出産による骨代謝状態の変化 (2017)
  • Author(s): 宮本健史，中村雅也，松本守雄
  • Organizer: 第９０回日本整形外科学会学術総会
• [Presentation] 骨代謝研究と骨粗鬆症研究の展開 (2016)
  • Author(s): 宮本健史
  • Organizer: 第３1回日本整形外科学会基礎学術総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] 筋萎縮研究の最前線 不動性筋萎縮の発症機構 (2016)
  • Author(s): 宮本健史、松本守雄、中村雅也
  • Organizer: 第３1回日本整形外科学会基礎学術総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] 骨代謝研究と骨粗鬆症研究の展開 骨粗鬆症と骨代謝研究の接点 (2016)
  • Author(s): 宮本健史、松本守雄、中村雅也
  • Organizer: 第３1回日本整形外科学会基礎学術総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] 関節炎疾患における単球系細胞の役割 (2016)
  • Author(s): 宮本健史
  • Organizer: 第４４回日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] ビタミンDと骨粗鬆症 (2016)
  • Author(s): 宮本健史
  • Organizer: 第３４回日本骨代謝学会学術集会・第３回アジア太平洋骨代謝学会議
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-07-20
  • Invited
• [Presentation] 骨代謝と骨粗鬆症 (2016)
  • Author(s): 宮本健史
  • Organizer: 第２回日本骨免疫学会
  • Place of Presentation: ホテルモントレ沖縄（沖縄県国頭郡）
  • Year and Date: 2016-07-06
  • Invited
• [Presentation] 臨床応用を見据えた骨代謝研究 (2015)
  • Author(s): 宮本健史、松本守雄、中村雅也
  • Organizer: 第３０回日本整形外科学会基礎学術総会
  • Place of Presentation: ANAクラウンプラザホテル（富山県富山市）
  • Year and Date: 2015-10-22
• [Presentation] 病態形成における破骨細胞の役割 (2015)
  • Author(s): 宮本健史、松本守雄、中村雅也
  • Organizer: 第３０回日本整形外科学会基礎学術総会
  • Place of Presentation: ANAクラウンプラザホテル（富山県富山市）
  • Year and Date: 2015-10-22
• [Presentation] 骨代謝－骨はどのように調節されているか－ (2015)
  • Author(s): 宮本健史
  • Organizer: 第８８回日本整形外科学会学術集会
  • Place of Presentation: 神戸ポートピアホテル（兵庫県神戸市）
  • Year and Date: 2015-05-21
• [Presentation] 25(OH)D低値は３９～６５歳において若年齢層により顕著に認められる (2015)
  • Author(s): 宮本健史、勝山詠理、藤江厚廣、丹藤世身、渡辺隆一、戸山芳昭
  • Organizer: 第８８回日本整形外科学会学術集会
  • Place of Presentation: 神戸ポートピアホテル（兵庫県神戸市）
  • Year and Date: 2015-05-21