A basic study for controlling postmenopausal osteoporosis by targeting HIF1 alpha in osteoclasts

• Project/Area Number: 15K10490
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: Sato Yuiko 慶應義塾大学, 医学部(信濃町), 研究員 (70445443)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 骨粗鬆症 / 閉経後骨粗鬆症 / 破骨細胞

Outline of Final Research Achievements

Estrogen deficiency due to menopause is one of the most serious risks for osteoporosis development. We previously identified that HIF1α expressed in osteoclasts was a target for postmenopausal osteoporosis therapy. In the current study, we clarified that Raloxifene, Bazedoxifene, Tamoxifen and ED71, all of which are currently used for postmenopausal osteoporosis therapy, had HIF1α inhibiting activity in osteoclasts. We also demonstrated that HIF1α was expressed in osteoclasts under an androgen deficient condition in male osteoporosis model mice. We showed that decreased bone mineral density in androgen deficient male osteoporosis model mice was clearly blocked by administrating either Raloxifene, Bazedoxifene, Tamoxifen or ED71.

Research Products

• [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] 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] 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
• [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